High concentration formulation

ABSTRACT

The present disclosure provides high concentration formulations of cortexolone-I 7u-propionate suitable for treating 0 alopecia.

BACKGROUND

Alopecia is a group of disorders with multiple and varying etiologiesthat results in hair loss from the body. The most common form ofalopecia is androgenetic alopecia (“AGA”). AGA is also commonly calledalopecia androgenetica, male pattern baldness, or male-pattern orfemale-pattern hair loss. It has been reported that AGA affects roughly50% of men over 40. This form of alopecia may eventually affect up to80% of white men by the age of 70 and about half of all women. Hair lossis often a cause of great concern to a patient for cosmetic andpsychological reasons, but it can also be an important sign of systemicdisease.

AGA is a hereditary hair follicle disease that is alsoandrogen-dependent. Dihydrotestosterone, in particular, plays a majorrole in the development and progression of AGA. Hair loss with AGA isprogressive such that patients with disease experience a reduction inthe normal 4:1 terminal-to-vellus hair ratio over a period of time.During this process, terminal hairs are converted to indeterminate hairsand finally into vellus hairs. Men present with hair thinning in thetemporal areas, which advances to the crown (vertex) area as the AGAprogresses. Women usually have more diffuse thinning on the crown area,and less commonly present with a male-type pattern.

In vivo, AGA is characterized by increased levels and activity of5α-reductase isoenzymes. These enzymes convert testosterone (T) into itsactive metabolite dihydrotestosterone (DHT). High concentrations of DHTat the hair-follicle level, due to increased binding capacity of thehormone to hair-follicle androgen receptors, shorten the hair cycle andgradually miniaturize scalp follicles. Following miniaturization of thefollicles, fibrous tracts remain. These DHT-dependent effects areconsidered, in most cases, reversible, such that AGA may be susceptibleto medical treatment with drugs able to reduce DHT production, or toantagonize DHT/T interaction with hair-follicle androgen receptors.

Current medical management of AGA comprises surgical and pharmacologicaltreatment options. The most common form of surgical intervention for AGAis hair transplantation. This procedure has been performed successfullyfor the past four decades. Hair transplantation involves harvestingintact hair follicles from within a safe donor area (SDA) of a patient'sscalp by either follicular unit strip surgery (FUSS) or follicular unitextraction (FUE). Refinements to these procedures over the last decadehave led to markedly improved hair survival and more natural appearingresults.

Although cosmetic results after surgery are often satisfactory, surgerycan only be performed when a sufficient quantity of donor plugs (orfollicles) are available to cover the balding area(s). Additionally,hair transplantation is generally reserved for patients who haveexperienced massive hair loss and for patients in whom AGA is not stillevolving. In younger patients, for example, hair transplantation isgenerally not recommended because androgens, particularly DHT, can acton the newly transplanted follicles resulting in same thinning andeventual hair loss that affected the originally present follicles. Forthis reason, at the initial onset and in the initial phases of the AGA,pharmacological intervention is preferred.

Currently, only two medicinal products are approved for treatment ofAGA: minoxidil (sold commercially as ROGAINE® and its generic forms) andfinasteride (sold commercially as PROPECIA®). Minoxidil, which isformulated as a topical drug product, is currently available at twostrength levels—2% (topical solution) and 5% (as a topical solution orfoam). To exert its effect minoxidil needs to be transformed into itsactive metabolite, minoxidil sulfate, by the enzyme sulfotransferase.This enzyme is present in the outer root sheath of anagen follicles.

Although the exact mechanism by which minoxidil promotes hair growth isstill unclear, it is believed that minoxidil sulfate opens ATP-sensitivepotassium channels in cell membranes resulting in vasodilation.Vasodilation, however, does not appear to be responsible forminoxidil-induced hair growth. Other possible effects of minoxidil onhair follicles include: a) increased expression of vascular endothelialgrowth factor (VEGF) mRNA in the dermal papilla, which indicates thatthe drug induces angiogenesis in the dermal papilla; b) activation ofcytoprotective prostaglandin synthase-1, a cytoprotective enzyme thatstimulates hair growth; and c) increased expression of hepatocyte growthfactor (HGF), which is an hair growth promoter.

In various clinical trials, minoxidil was found to be effective insignificantly improving total hair count and non-vellus hair count after6 to 12 months of treatment, in comparison to placebo. Moreover,minoxidil preparations are well tolerated, with only mild side effects.Despite these beneficial effects, minoxidil does not reducedihydrotestosterone (DHT) or the enzyme responsible for its accumulationaround the hair follicle, 5-alpha reductase—the primary mediator of malepattern baldness in genetically susceptible individuals. As a result,when treatment is stopped, DHT shrinks and ultimately destroysgenetically predisposed hair follicles.

Finasteride, on the other hand, inhibits 5-alpha reductase type II,which is responsible for transforming testosterone into DHT at thefollicle. Finasteride is administered orally in a 1 mg tabletformulation. A single oral administration of finasteride 1 mg decreasesserum DHT as well as scalp DHT up to 70% compared to baseline. Inseveral published clinical trials, finasteride 1 mg was found to beeffective in significantly improving the total hair count in comparisonto placebo after 6 months of treatment. The significant increase intotal hair counts, in comparison to placebo, in patients under treatmentwith finasteride 1 mg were maintained in long term treatments (up to 60months).

Even though finasteride effectively stops hair loss and improves newhair growth, there are possible adverse effects associated with its use.Foremost, finasteride is contraindicated in women due to suspectedteratogenic effects. Thus, women who are or may become pregnant,regardless of whether they suffer from AGA, are strongly cautioned toavoid contact with broken or crushed tablets. Additionally, becausefinasteride is distributed systemically, it not only reduces DHT levelsat the hair follicle, but in the plasma as well. This systemic activityis responsible for finasteride's main side effects, which includedecreased libido, erectile dysfunction (impotence), ejaculationdisorders, and decreased volume of ejaculate. Other less common sideeffects include breast swelling, palpitations, pain in testicles,persistent decrease in sex drive after discontinuation, infertility, anddepression.

In view of the deficiencies and drawbacks associated with finasterideand minoxidil therapies, it is apparent that there is a need in the artfor new methods and active agents for treating alopecia, and inparticular, AGA.

BRIEF SUMMARY

Cortexolone-17α-propionate(17α-propionyloxy-21-hydroxy-pregna-4-ene-3,20-dione) is a known topicalantiandrogen that displaces androgenic hormones from binding with theirreceptors. It is known to be suitable for treating acne, alopecia, andother diseases of skin and cutaneous appendages. See, e.g., U.S. Pat.Nos. 8,143,240 and 8,865,690. The compound is also known to exist inseveral distinct crystalline polymorphs, each having unique properties.See, e.g., U.S. Pat. No. 8,785,427. Each of these patents isincorporated herein by reference in its entirety.

Although certain formulations of cortexolone-17α-propionate have beendisclosed in the art, these formulations were limited to a concentrationof less than 2% by weight due to inherent solubility limitations of theactive and concerns that the administration of higher concentrationscould lead to greater and unwanted systemic exposure to the activeand/or its metabolites—particularly after repeated administration.

Despite these concerns, it has now been unexpectedly discovered that itis possible to prepare pharmaceutical formulations comprisingcortexolone-17α-propionate as the therapeutic agent for topicaladministration at concentrations of greater than 2% by weight. Thesepharmaceutical formulations have favorable characteristics for thetreatment of alopecia and provide optimal topical delivery of thetherapeutic agent as evidenced by the pharmacokinetic profiles describedherein. In particular, these pharmacokinetic profiles show that theformulations described herein advantageously maximize topical deliveryof cortexolone-17α-propionate in the skin and/or in the scalp whilesimultaneously minimizing systemic exposure tocortexolone-17α-propionate or any of its metabolites. As a result ofsuch drug disposition, an advantageous clinical result can be realizedafter daily topical administration for an appropriate amount of time,such as a few days, weeks, or months. Moreover, it has also beendiscovered that the pharmaceutical formulations described herein possessfavorable stability profiles, allowing for finished product storage atroom temperature for at least two years.

In certain embodiments the present disclosure provides a method oftreating alopecia in a patient in need thereof, comprising topicallyadministering to the patient a pharmaceutical formulation comprising atleast 2.1 weight percent cortexolone-17α-propionate and one or morepharmaceutically acceptable solvents.

In certain embodiments, the pharmaceutical formulation comprises fromabout 2.1 weight percent to about 20 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises from about 2.1 weight percent to about 17 weightpercent cortexolone-17α-propionate. In other embodiments, thepharmaceutical formulation comprises from about 2.5 weight percent toabout 17 weight percent cortexolone-17α-propionate. In otherembodiments, the pharmaceutical composition comprises from about 2.5weight percent to 15 weight percent cortexolone-17α-propionate. In otherembodiment, the pharmaceutical composition comprises from about 3 weightpercent to about 15 weight percent cortexolone-17α-propionate. In otherembodiments, the pharmaceutical formulation comprises about 6 weightpercent cortexolone-17α-propionate. In other embodiments, thepharmaceutical formulation comprises about 7 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 7.5 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 8 weight percent cortexolone-17α-propionate.In other embodiments, the pharmaceutical formulation comprises about 9weight percent cortexolone-17α-propionate. In other embodiments, thepharmaceutical formulation comprises about 10 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 11 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 12 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 13 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 14 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 15 weight percentcortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation comprises fromabout 2.1 weight percent to about 5.5 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 2.5 weight percentcortexolone-17α-propionate. In other embodiments, the pharmaceuticalformulation comprises about 3 weight percent cortexolone-17α-propionate.In other embodiments, the pharmaceutical formulation comprises about 4weight percent cortexolone-17α-propionate. In still other embodiments,the pharmaceutical formulation comprises about 5 weight percentcortexolone-17α-propionate. In still further embodiments, thepharmaceutical formulation comprises about 5.5 weight percentcortexolone-17α-propionate. In yet another embodiment, thepharmaceutical formulation comprises 5 weight percentcortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation is a liquid orsemi-solid formulation. In a further embodiment, the pharmaceuticalformulation is a solution, a suspension, an emulsion, a microemulsion, acream, a gel, a foam, or an ointment.

In certain embodiments, the pharmaceutical formulation is anhydrous andcontains less than about 5 weight percent water. In further embodiments,the pharmaceutical formulation is a solution.

In certain embodiments, the formulation provides a mean C_(max) ofcortexolone-17α-propionate of about 0.5 to about 3 ng/ml after topicalapplication of a single dose. In certain embodiments, the mean C_(max)of cortexolone-17α-propionate after administration of a single topicaldose is about 0.5 to about 1.5 ng/ml. In other embodiments, the meanC_(max) of cortexolone-17α-propionate after administration of a singletopical dose is 1.04±0.41 ng/ml.

In still other embodiments, the formulation provides a mean C_(max) ofcortexolone-17α-propionate of less than about 3 ng/ml after topicalapplication of a single dose comprising about 50 mg ofcortexolone-17α-propionate.

In some embodiments, the formulation provides a mean T_(max) ofcortexolone-17α-propionate of less than about 20 hours afteradministration of a single topical dose. In other embodiments, theformulation provides a mean T_(max) of cortexolone-17α-propionate ofless than about 15 hours after administration of a single topical dose.In yet another embodiment, the formulation provides a mean T_(max) ofcortexolone-17α-propionate of less than about 12 hours afteradministration of a single topical dose. And in yet another embodiment,the formulation provides a mean T_(max) of cortexolone-17α-propionate ofabout 6.22±5.17 hours after topical administration of a single dosecomprising about 50 mg of cortexolone-17α-propionate.

In certain embodiments, the formulation provides a mean AUC_(0-t) ofless than about 25 (ng*h)/ml after topical administration of a singledose comprising about 50 mg of cortexolone-17α-propionate. In otherembodiments, the formulation provides a mean AUC_(0-t) of less thanabout 20 (ng*h)/ml after topical administration of a single dosecomprising about 50 mg of cortexolone-17α-propionate. And in still otherembodiments, the formulation provides a mean AUC_(0-t) of about15.69±4.3 (ng*h)/ml after topical administration of a single dosecomprising about 50 mg of cortexolone-17α-propionate.

In some embodiments, the formulation provides a mean steady-stateC_(max) of cortexolone-17α-propionate of about 3.82±1.34 ng/ml aftertopical administration of a single dose comprising about 50 mg ofcortexolone-17α-propionate.

In other embodiments, the formulation provides a mean steady-stateT_(max) of cortexolone-17α-propionate of about 4.38±1.96 hours aftertopical administration of a single dose comprising about 50 mg ofcortexolone-17α-propionate.

In some embodiments, the formulation provides a mean steady-stateAUC_(0-t) of about 37.37±12.36 (ng*h)/ml after topical administration ofa single dose comprising about 50 mg of cortexolone-17α-propionate.

In some embodiments, the formulations of the invention provide a meanchange from baseline in Target Area Hair Count equal to or higher than 8hairs/cm² after 6 months of daily or BID application.

In some embodiments, the alopecia is androgenetic alopecia, alopeciaareata, telogen effluvium, anagen effluvium, traction alopecia, or acombination of any of the foregoing. In certain embodiments, thealopecia areata is selected from the group consisting of diffusealopecia areata, alopecia areata monolocularis, alopecia areatamultilocularis, ophiasis, alopecia totalis, and alopecia universalis.

In some embodiments, the alopecia is androgenetic alopecia.

In some embodiments, the formulation further comprises at least oneantioxidant, at least an emulsifier, or a combination of the foregoing.

In some embodiments, the formulation is administered once or twicedaily.

In some embodiments, the formulation is a liquid.

In some embodiments, from about 0.2 to about 2.0 ml of the formulationare administered during each application.

In a further embodiment, the present disclosure provides a topicalpharmaceutical formulation comprising cortexolone-17α-propionate at aconcentration of at least 2.1 weight percent, and one or morepharmaceutically acceptable solvents.

In certain embodiments, the formulation comprises from about 2.1 weightpercent to about 20 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises from about 2.1 weight percent toabout 17 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises from about 2.5 weight percent toabout 17 weight percent cortexolone-17α-propionate. In otherembodiments, the composition comprises from about 2.5 weight percent to15 weight percent cortexolone-17α-propionate. In other embodiment, thecomposition comprises from about 3 weight percent to about 15 weightpercent cortexolone-17α-propionate. In other embodiments, theformulation comprises about 6 weight percent cortexolone-17α-propionate.In other embodiments, the formulation comprises about 7 weight percentcortexolone-17α-propionate. In other embodiments, the formulationcomprises about 7.5 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises about 8 weight percentcortexolone-17α-propionate. In other embodiments, the formulationcomprises about 9 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises about 10 weight percentcortexolone-17α-propionate. In other embodiments, the formulationcomprises about 11 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises about 12 weight percentcortexolone-17α-propionate. In other embodiments, the formulationcomprises about 13 weight percent cortexolone-17α-propionate. In otherembodiments, the formulation comprises about 14 weight percentcortexolone-17α-propionate. In other embodiments, the formulationcomprises about 15 weight percent cortexolone-17α-propionate.

In certain embodiments, the formulation comprisescortexolone-17α-propionate at a concentration from about 2.1 weightpercent to about 5.5 weight percent. In other embodiments, theformulation comprises about 2.5 weight percentcortexolone-17α-propionate. In other embodiments, the topicalpharmaceutical formulation comprises about 3 weight percentcortexolone-17α-propionate. In another embodiment, the pharmaceuticalformulation comprises about 4 weight percent cortexolone-17α-propionate.In still another embodiment, the pharmaceutical formulation comprisesabout 5 weight percent cortexolone-17α-propionate. In yet a furtherembodiment, the pharmaceutical formulation comprises about 5.5 weightpercent cortexolone-17α-propionate. And in yet another embodiment, thepharmaceutical formulation comprises 5 weight percentcortexolone-17α-propionate.

In certain embodiments, the pharmaceutical formulation is a liquid orsemi-solid formulation. In some embodiments, the liquid or semi-solid,formulation is a solution, a suspension, an emulsion, a microemulsion, acream, a gel, a foam, or an ointment.

In some embodiments, the pharmaceutical formulation is anhydrous andcomprises less than about 5 percent water by weight. In otherembodiments, the pharmaceutical formulation is anhydrous and comprisesless than about 3 percent water by weight.

In some embodiments, the topical pharmaceutical formulation is asolution.

In some embodiments, the formulation provides a mean steady-stateC_(max) of less than about 7.0 ng/ml of cortexolone-17α-propionate uponthe application of an amount of the formulation including about 50 mg ofcortexolone-17α-propionate.

In other embodiments, the formulation provides a mean steady-stateT_(max) of cortexolone-17α-propionate of less than about 8.0 hours, uponthe application of an amount of the formulation including about 50 mg ofcortexolone-17α-propionate.

In certain embodiments, the formulation provides an AUC_(T) ofcortexolone-17α-propionate of less than about 64.1 (ng*h)/ml, upon theapplication of an amount of the formulation including about 50 mg ofcortexolone-17α-propionate

In certain embodiments, the formulation is for use in the treatment ofalopecia.

In certain embodiments, the one or more pharmaceutically acceptablesolvents are selected from the group consisting of a polyol, a polyolether, and a C₁-C₇ alcohol. In some embodiments, the C₁-C₇ alcohol isethanol, isopropanol, or methanol. In other embodiments, the C₁-C₇alcohol is ethanol. In certain embodiments, the ethanol is 96°. In someembodiments, the ethanol is absolute ethanol.

In some embodiments, the polyol is selected from the group consisting ofethylene glycol, propylene glycol, glycerol, and hexanetriol. Inparticular embodiments, the polyol is propylene glycol.

In certain embodiments, the polyol ether is selected from the groupconsisting of polypropylene glycol, polyethylene glycol,polyethylene-polypropylene triblock copolymers, dipropylene glycol, anddiethylene glycol monoethyl ether. In particular embodiments, the polyolether is diethylene glycol monoethyl ether.

In some embodiments, polyol is propylene glycol, the polyol ether isdiethylene glycol monoethyl ether, and the C₁-C₇ alcohol is ethanol.

In certain embodiments, formulation is anhydrous and contains less than5% water by weight or less than 3% water by weight.

In other embodiments, the formulation further comprises an emulsifier.

In certain embodiments, the formulation further comprises anantioxidant. In some embodiments, the antioxidant is selected from thegroup consisting of butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), ascorbyl palmitate, ascorbic acid, alphatocopherol, and propyl gallate. In certain embodiments, the antioxidantascorbyl palmitate.

In certain embodiments, the emulsifier is selected from the groupconsisting of PEG-15 hydroxystearate (also known aspolyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40oleate, polysorbate 20, polysorbate 60, polysorbate 80, PEG-20cetostearyl ether, polyoxyl 25 cetostearyl, cetomacrogol 1000, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate propyleneglycol esters of fatty acids, polyglycerol esters of fatty acids,polyoxyl 5 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil,polyoxyl 40 hydrogenated castor oil, caprylocapryl polyoxyil-8glycerides; caprylocaproyl polyoxylglycerides, lauroylpolyoxylglycerides, oleoyl polyoxylglycerides, and combinations of anyof the foregoing. In certain embodiments, the emulsifier is polysorbate80.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulation asdescribed herein, wherein twice a day topical administration of theformulation for at least six months achieves hair growth comparable tohair growth observed upon administration of oral finasteride for thesame period of time. In one aspect, the method provides a reducedincidence of adverse effects selected from the group consisting ofdecreased libido, erectile dysfunction (impotence), ejaculationdisorders, and decreased volume of ejaculate.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulation asdescribed herein, wherein the topical administration of the formulationfor at least six months achieves a mean value of the change frombaseline in non-vellus Target Area Hair Count (TAHC) of about 12.7 incomparison with vehicle.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulation asdescribed herein, wherein the topical administration of the formulationfor at least six months achieves a weighted average Hair GrowthAssessment (HGA) score of about 0.30 in comparison with vehicle.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulations asdescribed herein, wherein the topical administration of the formulationfor at least six months achieves a weighted average Investigator'sGlobal Assessment (IGA) score of about 0.43 in comparison with vehicle.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulation asdescribed herein, wherein the topical administration of the formulationfor at least six months is free from systemic antiandrogenicside-effects.

In another embodiment, the present description provides a method oftreating alopecia, the method comprising topically administering to asubject in need thereof a topical pharmaceutical formulation asdescribed herein, wherein the topical administration of the formulationprovides

a mean change from baseline in Target Area Hair Count equal to or higherthan 9 hairs/cm² after 6 months of daily or BID application; or

a mean change from baseline in Target Area Hair Count equal to or higherthan 10 hairs/cm² after 6 months of daily or BID application; or

a mean change from baseline in Target Area Hair Count equal to or higherthan 11 hairs/cm² after 6 months of daily or BID application; or

a mean change from baseline in Target Area Hair Count equal to or higherthan 12 hairs/cm² after 6 months of daily or BID application; or

a weighted average HGA score equal to or higher than 0.20 after 6 monthsof daily or BID application; or

a weighted average HGA score equal to or higher than 0.30 after 6 monthsof daily or BID application; or

a weighted average HGA score equal to or higher than 0.40 after 6 monthsof daily or BID application; or

a weighted average IGA score equal to or higher than 0.10 after 6 monthsof daily or

BID application; or

a weighted average IGA score equal to or higher than 0.20 after 6 monthsof daily or

BID application; or

a weighted average IGA score equal to or higher than 0.30 after 6 monthsof daily or

BID application; or

a favorable (positive) HGA score in at least about 10% of subjects after6 months of daily or BID application; or

a favorable (positive) HGA score in at least about 20% of subjects after6 months of daily or BID application; or

a favorable (positive) HGA score in at least about 30% of subjects after6 months of daily or BID application; or

a favorable (positive) IGA score in at least about 10% of subjects after6 months of daily or BID application; or

a favorable (positive) IGA score in at least about 20% of subjects after6 months of daily or BID application; or

a favorable (positive) IGA score in at least about 30% of subjects after6 months of daily or BID application; or

a favorable (positive) IGA score in at least about 40% of subjects after6 months of daily or BID application.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofthe embodiments, will be better understood when read in conjunction withthe appended figures. For the purpose of illustration, the figures maydescribe the use of specific embodiments. It should be understood,however, that the compounds, formulations and compositions describedherein are not limited to the precise embodiments discussed or describedin the figures.

FIG. 1 depicts the frequency distribution of Hair Growth Assessment(HGA), performed by study subjects, in two treatment groups after 6months of treatment in the Phase 2 clinical study in males withandrogenic alopecia (AGA) described in Example 9.

FIG. 2 depicts the frequency distribution of Investigator's GlobalAssessment (IGA) for hair growth in two treatment groups after 6 monthsof treatment in the Phase 2 clinical study in males with AGA describedin Example 9.

DETAILED DESCRIPTION

The formulations described herein constitute a major improvement to thecurrently available therapies of alopecia, and specifically AGA, andwould allow the physicians to have an effective, valuable and safetreatment of alopecia, and in particular AGA.

It has been found that the pharmaceutical formulations for topicaladministration described herein provide an optimal topical delivery ofthe therapeutic agent cortexolone-17α-propionate and, when used in thetreatment of alopecia, and in particular AGA, are able to achievesimilar results, in terms of efficacy, as commercially availablefinasteride 1 mg tablets (PROPECIA®) per os once daily, with minimaladverse effects. PROPECIA® has been approved for the treatment of AGA. Acomparison of the effect of a formulation described herein and that ofPROPECIA® is provided in Example 11 based on the information availableon the US Food and Drug Administration website and provided in thePROPECIA® package insert.

The pharmaceutical formulations described herein minimize systemicexposure and thus are safe. The results of the study described inExample 9 of the experimental section demonstrate thatcortexolone-17α-propionate solution 5% was well tolerated locally. Theincidence of local tolerability signs was low and the incidence of“treatment-emergent” local tolerability signs was generally similaramong cortexolone-17α-propionate solution 5% and vehicle treatmentgroups. Most local tolerability signs were minimal/trace to mild inseverity. Scaling and pruritus were most frequently observed“treatment-emergent” signs, with fewer subjects having erythema,folliculitis, and hyperpigmentation. In addition, the incidence ofadverse events (AEs) was similar among the two treatment groups, withmost events typically mild in severity and not related to the testarticle. Importantly, no AEs that could be correlated to systemicantiandrogenic activity of cortexolone-17α-propionate (e.g. decrease oflibido, erectile dysfunction and ejaculation disorders) occurred duringthe 6-month treatment. The study of the Example 9 also confirms that theformulations described herein, when topically applied on the scalp, areoptimal for achieving a local delivery of the therapeutic agent,meanwhile avoiding its excessive systemic distribution, which may causethe occurrence of antiandrogenic effects in treated subjects. The lowlevels of circulating cortexolone-17α-propionate, following theapplication of cortexolone-17α-propionate on the scalp, is also evidentfrom the PK parameters exemplified in Example 6. At least this propertydifferentiates the formulations described herein from finasteride 1 mgtablets (PROPECIA®): as reported in the PROPECIA® package insert, thedrug has many side effects, such as decreased libido, erectiledysfunction (impotence), ejaculation disorders, and decreased volume ofejaculate. These adverse events of PROPECIA®, which are reported in 1%of the patients, are caused by the systemic antiandrogenic activityexerted by the therapeutic agent. Differently from PROPECIA®, theformulations described herein are able to maximize the delivery of thetherapeutic agent to the target site (i.e. the hair follicle),minimizing its systemic adsorption, which translates into apharmacological profile characterized by efficacy in promoting hairregrowth (due to local activity on hair follicles), with absence ofsignificant adverse events, including those due to systemicantiandrogenic effects.

It is evident, based on the studies described in the experimentalsection, that the formulations described herein represent a greatimprovement with respect to the currently available systemicantiandrogenic drug, PROPECIA®, for the treatment of AGA. An exemplaryformulation of the invention, disclosed in Example 4b, when tested in aphase II clinical trial in subjects affected by AGA (with topicalapplications twice daily on the scalp of the affected area for 6months), demonstrated to be effective in stimulating the hair growth, asassessed by the two co-primary endpoints (the mean change from baselinein non-vellus TAHC and the subject self-assessment HGA questionnaire),which had a larger magnitude of improvement with respect to the vehicle.As discussed in Example 11, topical administration of this exemplaryformulation of Example 4b provided a mean change in non-vellus TAHC at 6months which was almost identical to that of PROPECIA® at 6 months (12.7for formulation of Example 4b vs. 12.2 calculated from the publishedresults of two phase III clinical studies for Propecia®), withoutsystemic antiandrogenic effects that are known to be responsible of themain side effects of PROPECIA®, such as decreased libido, erectiledysfunction (impotence) and ejaculation disorders.

The articles “a,” “an,” and “the” are used herein to refer to one or tomore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used herein, the term “about” means±10% of the specified value,unless otherwise indicated.

As used herein, the phrases “active agent” and “therapeutic agent” areinterchangeable and refer to cortexolone-17α-propionate.

The term “alopecia” as used herein refers to, collectively, orindividually as specified, androgenetic alopecia (AGA), alopecia areata(including diffuse alopecia areata, alopecia areata monolocularis,alopecia areata multilocularis, ophiasis, alopecia totalis, and alopeciauniversalis), telogen effluvium, anagen effluvium, and tractionalopecia.

As used herein, the term “anhydrous” means substantially free of water,i.e. having less than about 5 weight percent water, and, in certainembodiments as specified herein, less than about 3 weight percent water.

As used herein, the term “antioxidant” includes those pharmaceuticallyacceptable antioxidants known to those of ordinary skill in the art.Examples include, but are not limited to, butylated hydroxytoluene(BHT), butylated hydroxyanisole (BHA), ascorbyl palmitate, ascorbicacid, alpha tocopherol (also known as Vitamin E), propyl gallate, andthe like.

As used herein, the phrase “area under the curve” or “AUC” refers to thearea under the curve defined by changes in the plasma concentration ofthe active agent (or one of its metabolites, as specified) over timefollowing the application of a dose of the active agent itself or aformulation comprising the same. “AUC_(0-∞)” is the area under theconcentration-time curve extrapolated from t₀ to infinity following theapplication of a dose. “AUC_(0-t)” is the area under theconcentration-time curve from time zero to time t following theapplication of a dose, wherein t is the last time point with ameasurable concentration. AUC_(τ) refers to mean steady-state AUC.

As used herein, the phrase “C₁-C₇ alcohol” refers to an alcohol havingup to 7 carbons that is suitable for use in a topical pharmaceuticalformulation. Examples of such C₁-C₇ alcohols include, but are notlimited to, methanol, ethanol, isopropanol, n-butanol, n-propanol,benzyl alcohol, and the like. Without wishing to be bound by anyparticular theory, it is believed that C₁-C₇ alcohols, and particularlyshort chain C₁-C₇ alcohols, like ethyl, propyl or isopropyl alcohols,exert a solubilizing activity on cortexolone-17α-propionate. It isfurther believed that such C₁-C₇ alcohols contribute to thespreadability of the formulations described herein.

As used herein, the term “C_(max)” refers to the maximum concentrationof an active agent, or a metabolite thereof, on a graph of the plasmaconcentration of the active agent (or its metabolite) vs. time. C_(maxτ)refers to the maximum concentration of an active agent, or a degradationproduct thereof, on a graph of the plasma concentration of the activeagent (or its degradation product or metabolite) vs. time when thesteady state level has been reached.

As used herein “cortexolone” (also known as “11-Deoxycortisol” or“Reichstein's substance”) refers to the compound having the structure:

As used herein “cortexolone-17α-propionate” refers to the compound17α-propionyloxy-21-hydroxy-pregna-4-ene-3,20-dione, which is equivalentto the chemical structure:

As used herein, the term “metabolite” refers to those compounds thatresult from the in vivo metabolism or degradation ofcortexolone-17α-propionate. Exemplary known metabolites include, but arenot limited to, cortexolone and tetrahydrocortexolone.

As used herein, the term “degradation product” refers to those compoundsthat result from the in vitro degradation of cortexolone-17α-propionate.Exemplary known cortexolone-17α-propionate degradation products include,but are not limited to, cortexolone-21-propionate and cortexolone.

As used herein the term “ester” refers to esterified organic solventsincluding, but not limited to, ethyl acetate and ethyl lactate.

As used herein the phrase “natural oil” refers to those oils isolablefrom natural sources. Exemplary natural oils include, but are notlimited to, almond oil, olive oil, cottonseed oil, safflower oil, andthe like

As used herein, the term “polyol” refers to organic molecules containingtwo or more hydroxyl groups. Exemplary polyols include, but are notlimited to, ethylene glycol, propylene glycol, glycerol, hexanetriol,and the like.

As used herein, the phrase “polyol ether” refers to a polyol ethersuitable for use in a topical pharmaceutical formulation. Exemplarypolyol ethers include, but are not limited to, polypropylene glycol,polyethylene glycol, polyethylene-polypropylene triblock copolymers,dipropylene glycol, diethylene glycol monoethyl ether, and the like.

As used herein, the phrase “penetration enhancer,” refers to thosepharmaceutically acceptable compounds that increase penetration of theactive agent. Exemplary penetration enhancers include, but are notlimited to, polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethylsulfoxide, pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycolmonoethyl ether (TRANSCUTOL®), dimethyl isosorbide, diethyl sebacate,azone, menthol, nerol, camphor, methyl salicylate, Tween 80, SDS,benzalkonium chloride, polyoxyl 40 hydrogenated castor oil (CREMOPHOR®RH40, KOLLIPHOR® RH40), didecyldimethylammonium bromide (DDAB),didecyltrimethylammonium bromide (DTAB), fatty acids esters such asisopropyl myristate, isopropyl palmitate and the like, fatty acids suchas oleic acid, palmitic acid, linoleic acid, and salts thereof, fattyalcohols such as oleyl alcohol, myristyl alcohol, stearyl alcohol andthe like, medium-chain triglycerides, and combinations of any of theforegoing.

As used herein, the term “solvent” means one or a mixture of more thanone pharmaceutically acceptable solvents suitable for topicalapplication, including without limitation, the scalp, that is used tosolubilize cortexolone-17α-propionate in a formulation described herein.

As used herein “tetrahydrocortexolone” refers to the compound having theChemical Abstract Service (CAS) Registry Number 68-60-0.

As used herein, the term “T_(max)” refers to the time at which maximumplasma concentration of an active agent (or metabolite thereof) isreached after application of the active agent. The term T_(max) refersto the time when the maximum concentration of an active agent, ormetabolite thereof, on a graph of the plasma concentration of the activeagent (or its metabolite) vs. time when the steady state level has beenreached

The terms “treat,” “treating,” and “treatment” refer to any indicia ofsuccess in the treatment or amelioration of an injury, disease, orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,disease, or condition more tolerable to the patient; slowing in the rateof degeneration or decline; or improving a patient's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subject parameters, including the results of a physicalexamination, neuropsychiatric examinations, or psychiatric evaluation.

The term “preventing” refers to keeping from happening, existing, oralternatively delaying the onset or recurrence of a disease, disorder,or condition to which such term applies, or of one or more symptomsassociated with a disease, disorder, or condition. The term “preventing”also refers to reducing the incidence of a disease, disorder orcondition. The term “prevention” refers to the act of preventing.

As used herein, the phrase “weight percent” is intended to encompass anddisclose embodiments wherein the weight percent is weight percent byvolume (w/v) and percentage of weight by total weight (w/w) for a givenvalue. By way of example, an embodiment comprising 10 weight percent ofelement “X” discloses embodiments comprising both 10 weight percent “X”(w/v) and 10 weight percent “X” (w/w). Similarly, and again by way ofexample, an embodiment comprising 10 weight percent “X,” 20 weightpercent “Y,” and 60 weight percent “Z,” discloses embodimentscomprising: a) 10 weight percent “X” (w/v), 20 weight percent “Y” (w/v),and 60 weight percent “Z” (w/v); and b) 10 weight percent “X” (w/w), 20weight percent “Y” (w/w), and 60 weight percent “Z” (w/w). The foregoingnotwithstanding, in certain embodiments, a value will be markedspecifically “(w/w)” or “(w/v).” In those instances, the value should beinterpreted as disclosing only the labeled value, i.e. only (w/w) oronly (w/v)—but not both.

As used herein, the terms “comprises,” “comprising,” “having,”“including,” “containing,” and the like are open-ended terms meaning“including, but not limited to.” To the extent a given embodimentdisclosed herein “comprises” certain elements, it should be understoodthat present disclosure also specifically contemplates and disclosesembodiments that “consist essentially of” those elements and that“consist of” those elements.

As used herein the terms “consists essentially of,” “consistingessentially of,” and the like are to be construed as a semi-closedterms, meaning that no other ingredients which materially affect thebasic and novel characteristics of an embodiment are included.

As used herein, the terms “consists of,” “consisting of,” and the likeare to be construed as closed terms, such that an embodiment “consistingof” a particular set of elements excludes any element, step, oringredient not specified in the embodiment.

As used herein, the terms “Target Area Hair Count” or “TAHC” refer tothe change, from baseline, in the number of non-vellus hairs in a targetarea of the scalp. The target area can be, for example, 1 cm² or acircle of a diameter of 1 inch (5.1 cm²).

As used herein, the terms “Hair Growth Assessment” or “HGA” refer to ascore given by the subject comparing the baseline standardized globalphoto of the subject's scalp with a “real time” standardized globalphoto.

As used herein, the terms “Investigator's Global Assessment” or “IGA”refer to a score given by an evaluator comparing the baselinestandardized global photo of the subject's scalp with a “real time”standardized global photo.

As used herein, the term “Bis In Die” or “BID” means “twice a day”.

As used herein, the term “allocation group” refers to a group of peopleparticipating in a clinical trial that are randomly allocated to eitherthe group receiving the treatment under investigation or to a groupreceiving standard treatment (or placebo treatment) as the control.

As used herein, the term “ethanol,” means ethyl alcohol, i.e. CH₃CH₂OH,and includes pure (absolute) ethanol and 96° ethanol, the latter beingethanol containing water in an amount typically ranging from about 4% toabout 5.1% by volume.

The present disclosure provides fully solubilized pharmaceuticalformulations of cortexolone-17α-propionate comprising a solvent and atleast 2.1 weight percent cortexolone-17α-propionate up to about 20weight percent cortexolone-17α-propionate, including all intermediatevalues there between. In particular embodiments, the formulation cancomprise at least 2.1 weight percent up to about 17 weight percentcortexolone-17α-propionate, at least 2.5 weight percent up to about 17weight percent cortexolone-17α-propionate, at least 2.5 weight percentup to about 15 weight percent cortexolone-17α-propionate, or at least 3weight percent up to about 15 weight percent cortexolone-17α-propionate.In other embodiments, the formulation can comprise about 6, about 7,about 7.5, about 8, about 9, about 10, about 11, about 12, about 13,about 14, or about 15 weight percent of cortexolone-17α-propionate.

The present disclosure also provides fully solubilized pharmaceuticalformulations of cortexolone-17α-propionate comprising a solvent and atleast 2.1 weight percent cortexolone-17α-propionate up to about 5.5weight percent cortexolone-17α-propionate, including all intermediatevalues there between. In particular embodiments, the formulation cancomprise at least 2.2 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.3 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.4 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.5 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.6 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.7 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.8 up to about 5.5 weight percentcortexolone-17α-propionate, at least 2.9 up to about 5.5 weight percentcortexolone-17α-propionate, or at least 3.0 up to about 5.5 weightpercent cortexolone-17α-propionate. In other embodiments, theformulation can comprise about 2.3, about 2.5, about 3, about 3.5, about4, about 4.5, about 5, or about 5.5 weight percentcortexolone-17α-propionate. In a particular embodiment, the formulationcan comprise about 5 weight percent of cortexolone-17α-propionate. Ineach of these embodiments, the cortexolone-17α-propionate is fullysolubilized in the formulation. As used herein, “fully solubilized”means at least 95 weight percent, at least 98 weight percent, at least99 weight percent, or at least 99.9 weight percent of thecortexolone-17α-propionate is solubilized in the formulation.

Cortexolone-17α-propionate solubility exceeding 2 weight percent has notbeen previously reported and was difficult to achieve. For Example, WO2009/019138 discloses formulations having up to 2 weight percentcortexolone-17α-propionate, but does not teach or suggest whether higherconcentration formulations can be prepared or how such formulationshould be prepared.

Similarly, Celasco, et al., Arzneim.-Forsch./Drug Res. 54, No. 12,881-886 (2004), teaches suspending a 5 mg sample ofcortexolone-17α-propionate in 0.2 ml suspending vehicle. But like WO2009/019138, Celasco is silent on whether fully solubilizedhigh-concentration formulations can or should be prepared.

In certain embodiments, the formulation is anhydrous and includes lessthan about 5 weight percent water. In further embodiments, the anhydrousformulation includes less than about 3 weight percent water.

In certain embodiments, the formulation can be a liquid (including, forexample, a solution or a suspension or an emulsion or a microemulsion)or can be semi-solid (including, for example, a cream, a gel, or anointment, or a foam). Regardless of the form of the formulation(solution, gel, emulsion, etc.), the formulation has a suitableconsistency to be spread on the scalp and/or on the skin.

In one embodiment, the formulation can be a liquid formulation.

In another embodiment, the formulation can be anhydrous. In anotherembodiment, the formulation can be a solution. In some embodiments, thesolution is anhydrous having less than about 5 weight percent water. Inother embodiments, the anhydrous solution has less than about 3 weightpercent water.

In one embodiment, the present disclosure provides a pharmaceuticalformulation suitable for topical administration wherein the formulationcomprises cortexolone-17α-propionate in an amount of at least 2.1 weightpercent and one or more pharmaceutically acceptable solvents.

In another embodiment, the present disclosure provides a pharmaceuticalformulation suitable for topical administration wherein the formulationcomprises cortexolone-17α-propionate in an amount ranging from about 2.1weight percent to about 20 weight percent and one or morepharmaceutically acceptable solvents. Suitable ranges and amounts ofcortexolone-17α-propionate in this aspect of the invention are describedabove in connection with topical pharmaceutical formulations comprisingcortexolone-17α-propionate.

In another embodiment, the present disclosure provides a pharmaceuticalformulation suitable for topical administration wherein the formulationcomprises cortexolone-17α-propionate in an amount ranging from about 2.1weight percent to about 5.5 weight percent and one or morepharmaceutically acceptable solvents. Suitable ranges and amounts ofcortexolone-17α-propionate in this aspect of the invention are describedabove in connection with topical pharmaceutical formulations comprisingcortexolone-17α-propionate.

In still another embodiment, the present disclosure provides apharmaceutical formulation suitable for topical administration for usein the treatment and/or prevention of alopecia, wherein the formulationcomprises cortexolone-17α-propionate in an amount of at least 2.1 weightpercent and one or more pharmaceutically acceptable solvents.

In another embodiment, the present disclosure provides a pharmaceuticalformulation suitable for topical administration for use in the treatmentand/or prevention of alopecia, wherein the formulation comprisescortexolone-17α-propionate in an amount ranging from about 2.1 weightpercent to about 20 weight percent and one or more pharmaceuticallyacceptable solvents. Suitable ranges and amounts ofcortexolone-17α-propionate in this aspect of the invention are describedabove in connection with topical pharmaceutical formulations comprisingcortexolone-17α-propionate.

In yet another embodiment, the present disclosure provides apharmaceutical formulation suitable for topical administration for usein the treatment and/or prevention of alopecia, wherein the formulationcomprises cortexolone-17α-propionate in an amount ranging from about 2.1weight percent to about 5.5 weight percent and one or morepharmaceutically acceptable solvents. Suitable ranges and amounts ofcortexolone-17α-propionate in this aspect of the invention are describedabove in connection with topical pharmaceutical formulations comprisingcortexolone-17α-propionate.

In another embodiment, the present disclosure provides a method fortreating and/or preventing alopecia in a mammal in need thereof, themethod comprising topically administering a effective amount of apharmaceutical formulation suitable for topical administration, whereinthe formulation comprises cortexolone-17α-propionate in an amount of atleast 2.1 weight percent and one or more pharmaceutically acceptablesolvents.

A further aspect of the invention is a method for treating and/orpreventing alopecia in a mammal in need thereof, said method comprisingthe topical administration of a therapeutic amount of a pharmaceuticalformulation suitable for topical administration, wherein the formulationcomprises cortexolone-17α-propionate in an amount ranging from about 2.1weight percent to about 20 weight percent and one or morepharmaceutically acceptable solvents. Suitable ranges and amounts ofcortexolone-17α-propionate in this aspect of the invention are describedabove in connection with topical pharmaceutical formulations comprisingcortexolone-17α-propionate.

A further aspect of the present invention is a method for treatingand/or preventing alopecia in a mammal in need thereof, said methodcomprising the topical administration of a therapeutic amount of apharmaceutical formulation suitable for topical administration, whereinsaid formulation comprises cortexolone-17α-propionate in an amountranging from about 2.1 weight percent to about 5.5 weight percent andone or more physiologically acceptable solvents. Suitable ranges andamounts of cortexolone-17α-propionate in this aspect of the inventionare described above in connection with topical pharmaceuticalformulations comprising cortexolone-17α-propionate.

In certain embodiments, the mammal is a human.

In particular embodiments, topical administration comprises applicationof the formulation to the skin and/or the scalp.

In particular embodiments, the alopecia is androgenetic alopecia (AGA),alopecia areata (including diffuse alopecia areata, alopecia areatamonolocularis, alopecia areata multilocularis, ophiasis, alopeciatotalis and alopecia universalis), telogen effluvium, anagen effluvium,and traction alopecia. In particular embodiments, the alopecia is AGA.

In certain embodiments, the pharmaceutical formulation can be in form ofa solution, a gel, a fluid ointment, a suspension, a microemulsion, or afoam.

In addition to the solvent and the specified amount ofcortexolone-17α-propionate, the formulation described herein can alsooptionally contain at least one penetration enhancer, and optionally atleast one pharmaceutically acceptable excipient.

In certain embodiments, the formulation can further include at least oneantioxidant, at least one emulsifier, or a combination of the foregoing.

The Solvent

In certain embodiments, the solvent can be anhydrous including less thanabout 5 weight percent water. In other embodiments, the solvent can beanhydrous and include less than about 3 weight percent water.

In certain embodiments, the solvent can be selected from the groupcomprising or the group consisting of: water, a C₁-C₇ alcohol, a polyolether, a polyol, a natural oil, an ester, tricaprylin(2,3-di(octanoyloxy)propyl octanoate), a medium-chain triglyceride,caprylocaproyl polyoxyl-8 glycerides, and combinations of any of theforegoing.

In some embodiments, the formulation can comprise at least about 50weight percent solvent. In other embodiments, the formulation cancomprise at least about 60 weight percent solvent. In other embodiments,the formulation can comprise at least about 70 weight percent solvent.In other embodiments, the formulation can comprise at least about 80weight percent solvent. In other embodiments, the formulation cancomprise at least about 85 weight percent solvent, at least about 90weight percent solvent, at least about 91 weight percent solvent, atleast about 92 weight percent solvent; at least about 93 weight percentsolvent; at least about 94 weight percent solvent; or at least about 95weight percent solvent.

In certain embodiments, the solvent can comprise a mixture of a C₁-C₇alcohol, a polyol ether, a polyol. In such embodiments, the formulationcan comprise from about 10 to about 50 weight percent of the polyolether; from about 5 weight percent to about 55 weight percent of thepolyol; and about 5 to about 50 weight percent of the C₁-C₇ alcohol. Ina particular embodiment, the mixture of the C₁-C₇ alcohol, the polyolether, and the polyol can be present at about a 1:1:1 ratio on a w/w/wbasis. In certain embodiments, each of the C₁-C₇ alcohol, the polyolether, and the polyol are present at about 30 weight percent.

In particular embodiments, the formulation can comprise from about 15 toabout 45 weight percent of the polyol ether; from about 20 to about 40weight percent of the polyol ether; from about 25 to about 35 weightpercent of the polyol ether; or from about 30 to about 35 weight percentof the polyol ether. In particular embodiments, the formulation cancomprise about 30 weight percent of the polyol ether. In otherembodiments, the formulation can comprise about 32 weight percent of thepolyol ether.

In particular embodiments, the polyol ether is selected from the groupcomprising or the group consisting of: polyethylene glycol,polypropylene glycol, polyethylene-polypropylene triblock copolymers,dipropylene glycol, diethylene glycol monoethyl ether (TRANSCUTOL®), andcombinations thereof.

When the polyol ether is a polyethylene glycol, it can be selected fromthe group comprising or the group consisting of: polyethylene glycol200, polyethylene glycol 300, polyethylene glycol 400, polyethyleneglycol 540, and polyethylene glycol 600. In particular embodiments, thepolyol ether can be polyethylene glycol 200. In other embodiments, thepolyol ether can be polyethylene glycol 400. In still other embodiments,the polyol ether can be diethylene glycol monoethyl ether.

In particular embodiments, the polyol can be selected from the groupcomprising or the group consisting of: propylene glycol, ethyleneglycol, glycerol, hexanetriol, and combinations thereof. In particularembodiments, the polyol can be glycerol. In other embodiments, thepolyol can be propylene glycol.

In particular embodiments, the polyol can be present in an amountranging from about 5 weight percent to about 55 weight percent of thetotal formulation; from about 10 weight percent to about 50 weightpercent of the total formulation; from about 20 weight percent to about45 weight percent of the total formulation; and in certain embodiments,from about 25 weight percent to about 40 weight percent. In a particularembodiment, the polyol comprises about 30 weight percent of the totalformulation. In a further embodiment, the polyol comprising about 30weight percent of the total formulation can be propylene glycol.

In some embodiments, the formulation can comprise from about 5 to about50 weight percent of the C₁-C₇ alcohol. In particular embodiments, theformulation can comprise from about 15 to about 45 weight percent of theC₁-C₇ alcohol; from about 20 to about 40 weight percent of the C₁-C₇alcohol; or from about 25 to about 35 weight percent of the C₁-C₇alcohol. In particular embodiments, the formulation can comprise about30 weight percent of the C₁-C₇ alcohol. In still further embodiments,the formulation can comprise the C₁-C₇ alcohol in an amount ranging fromabout 10 weight percent to about 40 weight percent, or from about 15weight percent to about 35 weight percent.

In particular embodiments, the C₁-C₇ alcohol is selected from the groupcomprising or the group consisting of: methanol, ethanol, isopropanol,n-butanol, n-propanol, and benzyl alcohol. In particular embodiments,the C₁-C₇ alcohol is ethanol. In some embodiments, the ethanol comprisesabout 30 weight percent of the total formulation. In other embodiments,the C₁-C₇ alcohol is isopropanol.

In some embodiments, the C₁-C₇ alcohol can contain a small waterfraction, generally in the range of from about 4 percent to about 5.1percent by volume. In embodiments wherein the formulation is anhydrous,the C₁-C₇ alcohol having from about 4 percent to about 5.1 percent waterby volume can be present in the formulation in an amount such that thewater content in the finished formulation itself is less than about 5weight percent or less than about 3 weight percent.

In certain embodiments, the solvent can comprise a polyol, a polyolether, and a C₁-C₇ alcohol. In particular embodiments, the solvent cancomprise ethanol as the C₁-C₇ alcohol, diethylene glycol monomethylether as the polyol ether, and propylene glycol as the polyol. Thesesolvents can be present in any acceptable ratio, but typically arepresent such that each is about 25 to about 35 weight percent of theformulation.

Penetration Enhancers

In certain embodiments, in addition to the solvent, the formulationsdisclosed herein can include one or more penetration enhancers. Withoutwishing to be bound by a particular theory, penetration enhancers arebelieved to beneficially affect delivery of the therapeutic agent intothe skin (including the scalp) and/or the hair follicles.Advantageously, and in some embodiments, the solvent or somecomponent(s) of the solvent act as a penetration enhancer. For example,in embodiments wherein the formulation comprises ethanol and/ordiethylene glycol monoethyl ether, these solvents can also act toenhance penetration of the active agent into the skin (including thescalp) and/or the follicles. The presence of ethanol and/or diethyleneglycol monoethyl ether notwithstanding, the formulations describedherein can optionally further include additional penetration enhancers.

Examples of further penetration enhancer that can be incorporated intoformulations described herein include, but are not limited to,polyoxyethylene alkyl ethers, polyoxyl glycerides, dimethyl sulfoxide,pyrrolidone, N-methyl-2-pyrrolidone, diethylene glycol monoethyl ether(TRANSCUTOL®), dimethyl isosorbide, diethyl sebacate, azone, menthol,nerol, camphor, methyl salicylate, Tween 80, SDS, benzalkonium chloride,polyoxyl 40 hydrogenated castor oil (CREMOPHOR® RH40, KOLLIPHOR® RH40),didecyldimethylammonium bromide (DDAB), didecyltrimethylammonium bromide(DTAB), fatty acids esters such as isopropyl myristate, isopropylpalmitate and the like, fatty acids such as oleic acid, palmitic acid,linoleic acid, and salts thereof, fatty alcohols such as oleyl alcohol,myristyl alcohol, stearyl alcohol and the like, medium-chaintriglycerides, and combinations of any of the foregoing.

In one embodiment, the penetration enhancer is dimethyl isosorbide. Inanother embodiment, the penetration enhancer is a mixture comprisingdimethyl isosorbide and diethylene glycol monoethyl ether. In anotherembodiment, the at least one penetration enhancer is dimethyl sulfoxide.

In certain embodiments, the penetration enhancer can be present in anamount ranging from about 1 weight percent to about 50 weight percentwith respect to the total weight of the formulation. In otherembodiments, the penetration enhancer can be present from about 2 weightpercent to about 40 weight percent with respect to the total weight ofthe formulation; or from about 5 weight percent to about 35 weightpercent with respect to the total weight of the formulation. Accordingto some embodiments, the skin penetration enhancer can be present in theformulation described herein in an amount of about 1% weight percent,about 2 weight percent, about 5 weight percent, about 10 weight percent,about 15 weight percent, about 20 weight percent, about 25 weightpercent, about 30 weight percent, about 35 weight percent, about 40weight percent, about 45 weight percent, or about 50 weight percent withrespect to the total weight of the formulation.

Other Ingredients

Because oxidation can result in degradation of the active agent, in someembodiments, the formulation can further include up to about 1 weightpercent of an antioxidant. The antioxidant can be selected from thegroup comprising or the group consisting of: BHT, BHA, ascorbylpalmitate, ascorbic acid, alpha tocopherol (also known as Vitamin E),propyl gallate, and combinations of any of the foregoing.

In particular embodiments, the formulation can include up to about 0.5weight percent of an antioxidant or include about 0.5 weight percentantioxidant. In particular embodiments, the antioxidant can be ascorbylpalmitate. In other embodiments, the antioxidant can be BHA. In stillother embodiments, the antioxidant can be BHT. In still furtherembodiments, formulation can include about 0.5 weight percent ascorbylpalmitate.

In some embodiments, the formulation can further include an emulsifier.Without wishing to be bound to any particular theory, it is believedthat emulsifiers, when present, assist or facilitate dissolution of anysolid substances, such as the active agent, in the formulation. In otherembodiments, however, the emulsifier can be present to facilitateincorporation of two non-miscible liquids into each other (e.g. anemulsion or microemulsion).

In other embodiments, and without wishing to be bound by any particulartheory, an emulsifier can increase product spreadability. For example,and without wishing to be bound to a particular theory, when theformulation is a liquid solution, the presence of a suitable amount ofan emulsifier is believed to decrease the surface tension between theformulation and the lipid environment of the superficial layer of theskin and/or scalp. This makes it easier to spread the formulation and isbelieved to assist penetration of the therapeutic agent into skin(including the scalp) and/or hair follicles.

In certain embodiments, the emulsifier can be selected from the groupcomprising or the group consisting of: polyethylene glycol (PEG)-fattyacid monoesters such as PEG-15 hydroxystearate (also known aspolyoxyl-15-hydroxystearate), PEG-30 stearate, PEG-40 laurate, PEG-40oleate and the like; polyoxyethylene sorbitan fatty acid esters such aspolysorbate 20, polysorbate 60, polysorbate 80 and the like;polyoxyethylene alkyl ethers such as PEG-20 cetostearyl ether, polyoxyl25 cetostearyl, cetomacrogol 1000 and the like; sorbitan fatty acidesters such as sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, and the like; propylene glycol esters of fatty acids;polyglycerol esters of fatty acids; polyoxyethylene castor oilderivatives such as polyoxyl 5 castor oil, polyoxyl 15 castor oil,polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil and thelike; caprylocapryl polyoxyil-glycerides; polyoxylglycerides such ascaprylocaproyl polyoxylglycerides, lauroyl polyoxylglycerides, oleoylpolyoxylglycerides, and the like; along with combinations of any of theforegoing.

In particular embodiments, the formulation can include the emulsifier inan amount of up to about 0.5 weight percent of the total formulation. Insome embodiments, the emulsifier can be present in an amount rangingfrom 0.05 to 0.2 weight percent. In still further embodiments, theformulation can include the emulsifier in an amount up to about 0.1weight percent or it can include about 0.1 weight percent emulsifier. Inparticular embodiments, the emulsifier can be polyoxyl 40 hydrogenatedcastor oil. In other embodiments, the emulsifier can bepolyoxyl-15-hydroxystearate. In particular embodiments, the emulsifiercan be polysorbate 80. In still further embodiments, the emulsifier ispresent in the formulation at about 0.1 weight percent.

Pharmacokinetic Parameters

It has been surprisingly found that the formulations described hereinprovide acceptable pharmacokinetics profiles of bothcortexolone-17α-propionate and/or its metabolites and that theformulations described herein appear to provide excellent local deliveryof the therapeutic agent while minimizing systemic exposure. This is abeneficial result because, without wishing to be bound by any particulartheory, it is believed that the active agent is most effective whendelivered to the hair follicles directly, rather than through thesystemic circulation. Thus, it is an advantage of formulations of thepresent disclosure to be able to deliver the active agent withsufficient penetration to reach the follicles, but without so muchpenetration as to be widely systemically available after topicalapplication.

For example, in certain embodiments, the formulations described hereinprovide a mean steady-state C_(max) of cortexolone-17α-propionate ofabout 2 ng/ml to about 6 ng/ml; of about 2.5 ng/ml to about 5.5 ng/ml;or of about 3 ng/ml to about 5 ng/ml. In certain embodiments the meansteady-state C_(max) of cortexolone-17α-propionate can be about 4 ng/ml,or about 3.8 ng/ml. In other embodiments, the mean steady-state C_(max)can be less than about 6 ng/ml, less than about 5 ng/ml, less than about4 ng/ml, less than about 3 ng/ml, or less than about 2 ng/ml.

In certain embodiments, the formulation described herein provides a meansteady-state T_(max) of cortexolone-17α-propionate of from about 2 toabout 7 hours; from about 2.5 to about 6.5 hours; from about 3 to about6 hours; from about 3.5 to about 5 hours; or from about 4 to about 5hours. In particular embodiments, the mean steady-state T_(max) ofcortexolone-17α-propionate can be about 4.5 or 4.4 hours. In certainembodiments, the mean steady-state T_(max) of cortexolone-17α-propionatecan be less than about 8 hours, less than about 7 hours, less than about6 hours, less than about 5 hours, or less than about 4 hours.

The present formulation also provides a desirable AUC_(τ) of from about20 (ng*h)/ml to about 55 (ng*h)/ml; of from about 25 (ng*h)/ml to about50 (ng*h)/ml; of from about 25 (ng*h)/ml to about 45 (ng*h)/ml; or fromabout 30 (ng*h)/ml to about 40 (ng*h)/ml. In certain embodiments, themean AUC_(τ) can be about 35 (ng*h)/ml or about 37 (ng*h)/ml. In otherembodiments, the AUC_(τ) can be less than about 55 (ng*h)/ml, less thanabout 45 (ng*h)/ml, less than about 40 (ng*h)/ml, or less than about 35(ng*h)/ml.

The present formulation also provides a desirable excretion profile forcortexolone-17α-propionate. For example, after initial topicalapplication of the formulation, in certain embodiments, less than about0.5 percent of the cortexolone-17α-propionate administered can bedetected in a patient's urine. In other embodiments, less than about0.4, less than about 0.35, less than about 0.3, or less than about 0.25,less than about 0.2, or less than about 0.15 percent of thecortexolone-17α-propionate can be detected in a given patient's urine.In certain embodiments, no cortexolone-17α-propionate is detectable in agiven patient's urine.

In certain embodiments, after steady state has been achieved, less thanabout 700 μg of the cortexolone-17α-propionate administered can bedetected in a patient's urine. In other embodiments, less than about650, less than about 600, less than about 500, less than about 400, lessthan about 300, or less than about 250 μg of thecortexolone-17α-propionate can be detected in a given patient's urine.In certain embodiments, even after steady state has been achieved, nocortexolone-17α-propionate can be detected in a given patient's urine.

In certain embodiments, cortexolone can also be detected in a patient'surine. For example, in certain embodiments after initial topicalapplication of the formulation less than about 0.5 μg of cortexolone canbe detected in a patient's urine. In other embodiments, less than about0.4, less than about 0.35, less than about 0.3, or less than about 0.25,less than about 0.2, or less than about 0.15 μg of cortexolone can bedetected in a given patient's urine. In certain embodiments, nocortexolone can be detected in a given patient's urine.

After steady state has been achieved, and in certain embodiments, lessthan about 2 μg of cortexolone can be detected in a patient's urine. Inother embodiments, less than about 1.75, less than about 1.5, less thanabout 1.25, less than about 1, less than about 0.75, or less than about0.5 μg of the cortexolone can be detected in a given patient's urine. Incertain embodiments, even after steady state has been achieved, nocortexolone can be detected in a given patient's urine.

In certain embodiments, tetrahydrocortexolone can also be detected in apatient's urine. For example, in certain embodiments after initialtopical application of the formulation less than about 150 μg oftetrahydrocortexolone can be detected in a patient's urine. In otherembodiments, less than about 125, less than about 100, less than about75, less than about 65, less than about 55, or less than about 50 μg oftetrahydrocortexolone can be detected in a given patient's urine. Incertain embodiments, no tetrahydrocortexolone can be detected in a givenpatient's urine.

After steady state has been achieved, and in certain embodiments, lessthan about 400 μg of tetrahydrocortexolone can be detected in apatient's urine. In other embodiments, less than about 350, less thanabout 325, less than about 300, less than about 225, less than about150, or less than about 230 μg of the tetrahydrocortexolone can bedetected in a given patient's urine. In certain embodiments, even aftersteady state has been achieved, no tetrahydrocortexolone can be detectedin a given patient's urine.

Modes of Administration

The formulations described herein can be administered according tovarying schedules. In one embodiment, the mode of administration of theformulations can be continuous. For example, the formulations can beapplied topically once a day, twice daily, three times a day, four timesa day, or more, as specified by a physician. In particular embodiments,a formulation described herein can be applied topically once a day ortwice daily. According to a particular embodiment, the formulationdescribed herein can be applied topically once a day. According toanother embodiment, the formulation described herein can be appliedtopically twice daily.

In certain embodiments, a dosing regimen can be tapered. That is, theformulation can be applied once a day for a first period of time, twicedaily thereafter for a second period of time, three times a daythereafter for a third period of time, and so on. In a particularembodiment, the formulation can be applied once a day on the first day,and twice daily thereafter, with the appropriate duration of treatmentdetermined by a subject's physician.

In certain embodiments, the formulation can be applied over the courseof a period of days, weeks, or months. For example, the formulation canbe applied one, two, three, four, or five times a day for up to: 1, 2,3, 4, 5, 6, or 7 days; about 2 weeks, about 3 weeks, or about 4 weeks;about 2 months, about 3 months, about 4 months, about 5 months, about 6months, about 7 months, about 8 months, about 9 months, about 10 months,about 11 months, about a year (i.e. about 12 months), about 13 months,about 14 months, about 15 months, about 16 months, about 17 months,about 18 months, about 19 months, about 20 months, about 21 months,about 22 months, about 23 months or about 24 months. According to aparticular embodiment, the formulation can be applied once on the firstday and twice daily thereafter for about 4 weeks.

In another embodiments, the formulation can be topically applied to thescalp once a day for 1 month, once a day for 2 months, once a day for 3months, once a day for 4 months, once a day 5 months, once a day for 6months, once a day for 8 months, once a day for 12 months, once a dayfor 14 months, once a day for 16 months, once a day for 18 months, oncea day for 20 months, once a day for 22 months, or once a day for 24months. In certain embodiments, the formulation can be topically appliedon the scalp once daily for 6 months. In certain embodiments, theformulation can be topically applied on the scalp once daily for 12months.

In other embodiments, the formulation can be topically applied on thescalp twice daily for about 1 month, for about 2 months; for about 3months; for about 4 months; for about 5 months; for about 6 months, forabout 8 months, for about 12 months, for about 14 months, for about 16months, for about 18 months, for about 20 months, for about 22 months,or for about 24 months. In certain embodiments, the formulation can betopically applied on the scalp twice daily for 6 months. In certainembodiments, the formulation can be topically applied on the scalp twicedaily for 12 months.

In other embodiments, the formulation can be applied more than twicedaily (i.e. TID, QID, etc) for about 1 month, for about 2 months; forabout 3 months; for about 4 months; for about 5 months; for about 6months, for about 8 months, for about 12 months, for about 14 months,for about 16 months, for about 18 months, for about 20 months, for about22 months, or for about 24 months. In certain embodiments, theformulation can be topically applied on the scalp more than twice daily(i.e. TID, QID, etc) for 6 months. In certain embodiments, theformulation can be topically applied on the scalp more than twice daily(i.e. TID, QID, etc) for 12 months.

In another embodiment, the mode of administration of the formulationscan be cyclic. For example, the formulations can first be applied in acontinuous way as described above for a desired period of time, theapplication is then discontinued for a period of time, such as a fewdays, and then the application of the formulations is started again asdescribed above. The treatment period can include one or more cycleswhich can be the same or different. In certain embodiments, thetreatment period can be as follows: a) the formulation is topicallyapplied on the scalp for a period of time, such as 4 months, bycontinuous administration, b) the application is discontinued for a fewdays, such as 2-5 days, and 3) the topical application is continued foran additional period of time, such as 6 months.

The amount of cortexolone-17α-propionate that can be applied to apatient in need thereof can vary. In some embodiments, about 400 mg ofcortexolone-17α-propionate can be applied, about 375 mg ofcortexolone-17α-propionate can be applied, about 350 mg ofcortexolone-17α-propionate can be applied, about 325 mg ofcortexolone-17α-propionate can be applied, about 300 mg ofcortexolone-17α-propionate can be applied, about 275 mg ofcortexolone-17α-propionate can be applied, about 250 mg ofcortexolone-17α-propionate can be applied, or about 225 mg ofcortexolone-17α-propionate can be applied. In some embodiments, about200 mg of cortexolone-17α-propionate can be applied, about 175 mg ofcortexolone-17α-propionate can be applied, about 150 mg ofcortexolone-17α-propionate can be applied, about 125 mg ofcortexolone-17α-propionate can be applied, about 100 mg ofcortexolone-17α-propionate can be applied, about 75 mg ofcortexolone-17α-propionate can be applied, about 50 mg ofcortexolone-17α-propionate can be applied, about 25 mg ofcortexolone-17α-propionate can be applied, about 12.5 mg ofcortexolone-17α-propionate can be applied, or about 6.25 mg ofcortexolone-17α-propionate can be applied. Determination of theappropriate amount of the formulation that should be administered to agiven patient in a single application is within the skill of theordinarily skilled physician.

In particular embodiments, the amount of cortexolone-17α-propionate in asingle application can range from about 20 mg to about 400 mg. In otherembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 350 mg. In otherembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 300 mg. In otherembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 250 mg.

In particular embodiments, the amount of cortexolone-17α-propionate in asingle application can range from about 20 mg to about 200 mg. In otherembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 170 mg. In otherembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 150 mg. In particularembodiments, the amount of cortexolone-17α-propionate in a singleapplication can range from about 20 mg to about 100 mg. In particularembodiments, the amount of cortexolone-17α-propionate in a singleapplication can be about 20 mg, about 25 mg, about 30 mg, about 35 mg,about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about75 mg, about 80 mg, about 85 mg, about 90 mg, or about 100 mg. Inanother embodiment, the amount of cortexolone-17α-propionate in a singleapplication can be about 25 mg. In another embodiment, the amount ofcortexolone-17α-propionate in a single application can be about 30 mg.In yet another embodiment, the amount of cortexolone-17α-propionate in asingle application can be about 50 mg. In yet another embodiment, theamount of cortexolone-17α-propionate in a single application can beabout 75 mg. In yet another embodiment, the amount ofcortexolone-17α-propionate in a single application can be about 80 mg.In yet another embodiment, the amount of cortexolone-17α-propionate in asingle application can be about 100 mg. In other embodiments, the amountof cortexolone-17α-propionate in a single application can be about 110mg, about 111 mg, about 112 mg, about 113 mg, about 114 mg, about 115mg, about 116 mg, about 117 mg, about 118 mg, about 119 mg, or about 200mg. In yet another embodiment, the amount of cortexolone-17α-propionatein a single application can be about 150 mg.

By way of example only, about 50 mg of cortexolone-17α-propionate couldbe administered in 1 ml of an embodiment of a formulation disclosedherein, wherein the formulation comprises about 5 weight percentcortexolone-17α-propionate.

In some embodiments, the formulation can be self-administered by thepatient once a day or twice daily. In particular embodiments, when theformulation is in liquid form having an active agent concentration ofabout 5 weight percent, the formulation can be self-administered once aday or twice daily at a dose ranging from about 0.2 to about 2.0 ml,from about 0.5 to about 1.5 ml, and in further embodiments at about 1ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 2.5 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 3 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 7.5 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 8 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 10 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 15 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

In other embodiments, when the formulation is in liquid form having anactive agent concentration of about 20 weight percent, the formulationcan be self-administered once a day or twice daily at a dose rangingfrom about 0.2 to about 2.0 ml, from about 0.5 to about 1.5 ml, and infurther embodiments at about 1 ml.

The formulation described herein can be applied to any body surface inneed of treatment, such as the scalp, face (e.g., the eyebrow,eyelashes, upper lip, lower lip, chin, cheeks, beard area, or mustachearea), arms, armpits, legs, chest, abdomen, or any combination of theforegoing. In certain embodiments, treatment is not delivered to theface. In other embodiments, the formulation can be applied to the scalp.

Efficacy Parameters

It has been surprisingly found that the pharmaceutical formulationsdescribed herein are able to maximize the delivery of the therapeuticagent cortexolone-17α-propionate to the target site (i.e. the hairfollicle), minimizing its systemic adsorption. Thus, it is an advantageof the pharmaceutical formulations of the present disclosure to be ableto deliver the active agent with sufficient penetration to reach thefollicles, but without so much penetration as to be widely systemicallyavailable after topical application. This translates into apharmacological profile characterized by efficacy in promoting hairregrowth (local activity on hair follicles), with absence of significantadverse events, including those due to systemic antiandrogenic effects(low systemic adsorption of the therapeutic agent).

In some embodiments, the formulations described herein provide a meanchange from baseline in Target Area Hair Count equal to or higher than 8hairs/cm² after 6 months of daily or BID application.

In other embodiments, the formulations described herein provide a meanchange from baseline in Target Area Hair Count equal to or higher than 9hairs/cm² after 6 months of daily or BID application.

In other embodiments, the formulations described herein provide a meanchange from baseline in Target Area Hair Count equal to or higher than10 hairs/cm² after 6 months of daily or BID application.

In other embodiments, the formulations described herein provide a meanchange from baseline in Target Area Hair Count equal to or higher than11 hairs/cm² after 6 months of daily or BID application.

In other embodiments, the formulations described herein provide a meanchange from baseline in Target Area Hair Count equal to or higher than12 hairs/cm² after 6 months of daily or BID application.

In some embodiments, the formulations described herein provide aweighted average HGA score equal to or higher than 0.20 after 6 monthsof daily or BID application.

In other embodiments, the formulations described herein provide aweighted average HGA score equal to or higher than 0.30 after 6 monthsof daily or BID application.

In some embodiments, the formulations described herein provide aweighted average HGA score equal to or higher than 0.40 after 6 monthsof daily or BID application.

In some embodiments, the formulations described herein provide aweighted average IGA score equal to or higher than 0.10 after 6 monthsof daily or BID application.

In other embodiments, the formulations described herein provide aweighted average IGA score equal to or higher than 0.20 after 6 monthsof daily or BID application.

In other embodiments, the formulations described herein provide aweighted average IGA score equal to or higher than 0.30 after 6 monthsof daily or BID application.

In some embodiments, the formulations described herein provide afavorable (positive) HGA score in at least about 10% of subjects after 6months of daily or BID application.

In other embodiments, the formulations described herein provide afavorable (positive) HGA score in at least about 20% of subjects after 6months of daily or BID application.

In other embodiments, the formulations described herein provide afavorable (positive) HGA score in at least about 30% of subjects after 6months of daily or BID application.

In some embodiments, the formulations described herein provide afavorable (positive) IGA score in at least about 10% of subjects after 6months of daily or BID application.

In other embodiments, the formulations described herein provide afavorable (positive) IGA score in at least about 20% of subjects after 6months of daily or BID application.

In other embodiments, the formulations described herein provide afavorable (positive) IGA score in at least about 30% of subjects after 6months of daily or BID application.

In other embodiments, the formulations described herein provide afavorable (positive) IGA score in at least about 40% of subjects after 6months of daily or BID application.

In some embodiments, the formulations described herein are effective instimulating the hair re-growth, providing the TAHC, HGA scores and IGAscores above disclosed, without exerting a systemic antiandrogenicactivity. Such formulations are devoid of side effects attributable tosystemic antiandrogenic effects. Said side effects include, but are notlimited to, decreased libido, erectile dysfunction (impotence),ejaculation disorders, and decreased volume of ejaculate.

Storage Stability

Storage stability is an important metric for pharmaceutical products. Ingeneral, greater stability means that a given formulation is both easierto transport and store, increasing the likelihood that it will bestocked by pharmacies and that patients will not have to be concernedwith special storage instructions. The formulations described hereinhave a desirable stability profile allowing for storage of the finalformulation for at least about 3 months, at least about 6 months, atleast about 9 months, at least about 12 months, at least about 15months, at least about 18 months, at least about 21 months, or at leastabout two years—each at room or refrigerated temperatures.

For example, one of the main degradation pathways ofcortexolone-17α-propionate is transesterification tocortexolone-21-propionate(17α-hydroxy-21-propionyloxy-pregna-4-ene-3,20-dione):

It has now been surprisingly discovered that by maintaining theformulations disclosed herein at a pH of less than about 6, and incertain embodiments, less than about 5, between about 4 and about 5, orat about 4, this degradation process can be dramatically slowed. Inparticular embodiments, the pH can be 4. The appropriate pH can beobtained via addition of a suitable amount of a pH modifier.

Acceptable pH modifiers include those pharmaceutically acceptableorganic and inorganic acids known to those of ordinary skill in the art.Examples of such acids, include, but are not limited to1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid;2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoicacid; 4-aminosalicylic acid; acetic acid; adipic acid; L-ascorbic acid;L-aspartic acid; benzenesulfonic acid; benzoic acid; (+)-camphoric acid;(+)-camphor-10-sulfonic acid; capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; D-glucoheptonic acid; D-gluconicacid; D-glucuronic acid; glutamic acid; glutaric acid; glycerophosphoricacid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid;isobutyric acid; lactic acid; lactobionic acid; lauric acid; maleicacid; L-malic acid; malonic acid; mandelic acid; methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid;phosphoric acid; proprionic acid; L-pyroglutamic acid; salicylic acid;sebacic acid; stearic acid; succinic acid; sulfuric acid; L-tartaricacid; thiocyanic acid; p-toluenesulfonic acid; and undecylenic acid. Inparticular embodiments, the pH modifying agent can be citric acid.

In certain embodiments, the formulations described herein can, at roomor refrigerated temperatures, have less than about 5 weight percentcortexolone-21-propionate or other degradation product after storage fora period of about 24 months.

While pH can be important to stability, it has also been discovered thataddition of an antioxidant to the formulation can assist in maintainingstorage stability. The antioxidant can be present in addition to a pHmodifier. But in some embodiments, the pH modifier can be substantiallyor completely absent. The antioxidant can be present in the amountsspecified elsewhere herein.

It has surprisingly found that a formulation containingcortexolone-17α-propionate as disclosed herein provides acceptablepharmacokinetics profiles of both cortexolone 17α-propionate and/or itsmetabolites, providing a therapeutically effective amount of thetherapeutic agent to the scalp and/or skin while minimizing systemicexposure. Without wishing to be bound to a particular theory, it isbelieved that the formulations disclosed herein deliver the therapeuticagent to the derma, with deeper penetration minimized by the nature ofthe formulations disclosed herein. This effect is evidenced in Franzcell data reported in Examples 6 and 7, below.

Thanks to such a favorable pharmacokinetic profile, with hightherapeutic levels of the therapeutic agent at the target site and lowlevels in the systemic circulation, the formulation as disclosed hereinis efficacious for treating alopecia, without significant adverseevents.

In addition, the formulation herein disclosed has an optimal stabilityprofile allowing a storage of the final product for at least two years(upon storage at refrigerated or room temperature, as defined byPharmaceutical Guidelines).

EXAMPLES

The formulations described herein are now further detailed withreference to the following examples. These examples are provided for thepurpose of illustration only and the embodiments described herein shouldin no way be construed as being limited to these examples. Rather, theembodiments should be construed to encompass any and all variationswhich become evident as a result of the teaching provided herein.

Example 1: Evaluation of Cortexolone-17α-Propionate Solubility

5 g of cortexolone-17α-propionate was added to 100 ml of each of thesolvents or solvent mixtures shown in Table 1, below, in an effort toproduce a 5% w/v solution of cortexolone-17α-propionate. In the examplesin Table 1, ethanol refers to ethanol 96°.

TABLE 1 Cortexolone-17α-propionate Solvent (v:v) Solubility at RoomTemperature Water Insoluble Ethanol Highly soluble TRANSCUTOL ® Verysoluble Propylene glycol Sparingly soluble Isopropyl myristate InsolubleIsopropyl palmitate, Insoluble Caprylocaproyl polyoxyl-8 glyceridesSparingly soluble NF (LABRASOL ®) TRANSCUTOL ®/water (1:1) InsolubleTRANSCUTOL ®/water/ethanol Soluble (1:1:1) Ethanol/propylene glycol(1:1) Soluble Ethanol/propylene glycol/ Very soluble TRANSCUTOL ®(1:1:1) Water/propylene glycol/ Insoluble TRANSCUTOL ® (1:1:1)Water/propylene glycol/ Soluble TRANSCUTOL ® (1:1:2)

As can be seen from the data in Table 1, water is an unsuitable solventfor cortexolone-17α-propionate when used alone or in a binary mixture.TRANSCUTOL® increased solubility of the therapeutic agent in eachmixture in which it was used. Ethanol was likewise found to readilysolubilize cortexolone-17α-propionate, but cannot be used alone due topossible burning after topical application as well its potential forabuse.

Example 2: Evaluation of pH on Cortexolone-17α-Propionate Stability

In a suitable container, under stirring, 50 g ofcortexolone-17α-propionate was dissolved in a mixture of TRANSCUTOL®(461 g) and ethanol 96° (200 g). After complete dissolution of thecortexolone-17α-propionate, water (283 g) was added slowly. Finally,polysorbate 80 (5 g) and Alpha tocopherols (Vitamin E) (1 g) were addedto the formulation. The natural pH of this formulation was measuredusing a standard pH electrode to be about 5.1.

The formulation was then split into three equal batches, each weighingabout 300 g. Citric acid was added to the first batch to lower the pH toabout 4. Sodium citrate was added the second batch to increase the pH toabout 6. The third batch, having a natural pH of about 5.1, was used asa control. The three batches were then subjected to a short termstability study at 30° C., with the results shown in Table 2.

TABLE 2 Cortexolone-21-propionate Contents* After 1 After 2 After 3 Timemonth months months pH 0 (30° C.) (30° C.) (30° C.) 4 0.04% 0.16% 0.26%0.37% 5.1 0.68% 1.48% 1.85% 1.80% 6 10.79% NA NA NA*Cortexolone-21-propionate contents calculated as (% (w/w) ofcortexolone-21-propionate)/(% (w/w) of cortexolone-17α-propionate × 100)

The above data clearly shows that production ofcortexolone-21-propionate is significantly lowered at a pH of about 4.

Example 3: Antioxidant Evaluation

To a formulation containing 5 weight percent cortexolone-17α-propionatein a mixture of TRANSCUTOL®, propylene glycol, and ethanol (96°) inratio of about 1:1:1 by weight, and further containing polysorbate 80 at0.1 weight percent, the following antioxidants were added: Alphatocopherols (Vitamin E) 0.3 weight percent; butylated hydroxyanisole(BHA) 0.01 weight percent, or ascorbyl palmitate 0.5 weight percent. Thethree formulations were then studied under short term stabilityconditions. The results are shown in Table 3.

TABLE 3 Total Impurities Contents (Impurity percent = (sum of the %(w/w) of each impurity)/% (w/w) of cortexolone 17-alpha propionate *100) After 1 After 2 After Anti- Time month months 3 months oxidant 0(30° C.) (30° C.) (30° C.) Alpha 0.62% 1.33% 1.56% 1.78% tocopherols(Vitamin E) BHA 1.37% 2.86% 2.57% NA Ascorbyl 0.05% 0.22% 0.29% 0.37%palmitate

Ascorbyl palmitate provided the least amount of total degradationproducts.

Example 4a: Anhydrous 5% w/w Solution

A 5 weight percent (w/w) solution of cortexolone-17α-propionate havingthe components shown in Table 4, below, was prepared by solubilizing thetherapeutic agent in the mixture of solvents followed by the addition ofthe antioxidant (ascorbyl palmitate) and the emulsifier (polysorbate80).

TABLE 4 Amount Amount (Kg/ Component (g/100 g) 15 Kg batch)Cortexolone-17α-propionate 5.00 0.75 Diethylene glycol monoethyl 31.504.725 ether Alcohol (Ethanol) 31.50 4.725 Ascorbyl palmitate 0.50 0.075Polysorbate 80 0.10 0.015 Propylene glycol 31.40 4.710

This formulation provided the stability profile (40° C./75% RH) shown inTable 5.

TABLE 5 Cortexolone- Cortexolone 17α- 21- Total Time propionatepropionate impurities point (% w/w) %* %* 0 5.108 0.07 0.13 1 month5.046 1.08 1.19 3 months 4.989 2.78 3.11 6 months 4.847 4.76 5.23*Percentages of cortexolone-21-propionate and total impuritiescalculated as noted in Examples 2 and 3.

Example 4b: Anhydrous 5% w/v Solution

A 5% (w/v) solution of cortexolone-17α-propionate having the componentsshown in Table 6, below, was prepared by solubilizing the therapeuticagent in the mixture of solvents followed by the addition of theantioxidant (ascorbyl palmitate) and the emulsifier (polysorbate 80).

TABLE 6 Amount (g/ Amount (Kg/ Amount (Kg/ Component 100 mL) 20 L batch)50 L batch) Cortexolone-17α-propionate 5.000 1.000 2.500 Diethyleneglycol monoethyl 30.000 6.000 15.000 ether (TRANSCUTOL ®) Alcohol(Ethanol) 30.000 6.000 15.000 Ascorbyl palmitate 0.500 0.100 0.250Polysorbate 80 0.100 0.020 0.050 Propylene glycol Q.s. to 100 mL Q.s. to20 L Q.s. to 50 L

Example 5: Aqueous 5% w/w Solution

A formulation of cortexolone-17α-propionate having the components shownin Table 7, below, was prepared by solubilizing the therapeutic agent inthe mixture of solvents followed by the addition of the antioxidant andthe emulsifier.

TABLE 7 Amount Amount Component (g/100 g) (Kg/15 Kg batch)Cortexolone-17α-propionate 5.00 0.750 TRANSCUTOL ® 46.10 6.915 Purifiedwater 28.30 4.245 Ethanol 20.00 3.00 Polysorbate 80 0.50 0.075 Alphatocopherols (vitamin E) 0.10 0.015 Citric acid, monohydrate Q.s. tobring the Q.s. to bring the pH to 4.0-4.5 pH to 4.0-4.5

The stability of this formulation at 40° C./75% RH is shown in Table 8.

TABLE 8 Cortexolone- 17α- Cortexolone propionate 21-propionate TotalTime point (% W/W) % impurities % 0 5.127 0.08 0.14 1 month  5.064 1.191.38 3 months 4.962 3.79 4.21 6 months 4.546 7.66 8.41

Based on the impurity profile, the formulation prepared in Example 4a ismore stable than the aqueous formulation of Example 5.

Example 6: Clinical Evaluation

The formulation described in Example 4b was studied in a clinical trialto evaluate its pharmacokinetic profile, safety, and tolerability.According to the study protocol, 1 ml of the formulation (correspondingto 50 mg of cortexolone-17α-propionate) was applied once a day on studyday 1 and then twice daily thereafter on study days 2-28 to the areas ofthe scalp suffering from alopecia. The formulation provided thepharmacokinetic profile shown in Tables 9 and 10 and the excretion datashown in Table 11. Statistical analyses were performed using SAS®version 9.1.3, service pack 4 for Windows and Phoenix WinNonLin 6.3,Pharsight Corporation, USA.

TABLE 9 PK parameters after single dose administration C_(max) AUC_(0-t)(ng/ml) T_(max) (h) (ng*h)/ml (N = 18) (N = 18) (N = 18) Mean (± SD)1.04 ± 0.41 6.22 ± 5.17 15.69 ± 4.30 Median 0.98 (0.57- 4.0 (4-24) 15.26(9.47- (range) 1.96) 24.53)

TABLE 10 PK parameters after repeated dose administration (steady state)AUC_(τ) C_(max) (ng/ml) T_(max) (h) (ng*h)/ml T_(1/2) (h) (N = 17) (N =17) (N = 17) (N = 16) Mean (± SD) 3.82 ± 1.34 4.38 ± 1.96 37.37 ± 12.3617.84 ± 9.12 Median 4.03 (1.77- 4.0 (0.5-8) 37.71 14.84 (7.93- (range)7.04) (18.39- 47.73) 64.11)

TABLE 11 Excretion parameters at 1^(st) and 55^(th) application 1^(st)Application 55^(th) Application Application (Day 1) (N = 18) (Day 28) (N= 17) Cortexolone-17α-propionate Parameter Total Free Total Free Analyte126.37 ± 48.99 0.16 ± 0.34 429.53 ± 178.24 2.72 ± 1.54 Excreted (μg) %Excreted  0.25 ± 0.10  0 ± 0 — — Cortexolone Analyte  0.06 ± 0.26  BLQL0.64 ± 0.74 BLQL Excreted μg) Tetra hydrocortexolone Analyte  71.45 ±21.36 BLQL 226.03 ± 100.10 0.46 ± 0.65 Excreted (μg)

Example 7: Franz Cell Diffusion Test 1

In an in vitro study, the skin penetration potential ofcortexolone-17α-propionate was compared to cyproterone acetate using astandard Franz cell. According to the protocol, 300 mg of each testformulations was applied as saturated solution with a concentrationranging from 0.7 to 1 weight (w/w) to 2.54 cm² of exposed skin area. Thereceptor chamber volume ranged from 4.75 ml to 6.4 ml of phosphatebuffered saline/fetal calf serum (2:1) containingpenicillin/streptomycin according to standard protocol, and wasmaintained at a temperature of 32° C.+/−1° C. Stirring was maintained at300 rpm.

The experiments were conducted for 48 h in triplicate. 100 μl fractionswere withdrawn at 5-7 time points during the 48 h test period. Afterwithdrawing a 100 μl fraction for analysis, it was replaced with freshreceiver fluid in an equal volume. At the end of the experiment, theskin was taken from the Franz cells and the skin's stratum corneum wasremoved by tape stripping (20×) with transparent adhesive tape (Koren,Spain).

The strippings were analyzed by dissolution in a mixture of propyleneglycol: oleyl alcohol 9:1. The resulting mixture was analyzed forconcentration of cyproterone acetate and cortexolone-17α-propionate,with the results provided in Table 12, below.

TABLE 12 Applied Skin concentration Permeation rate CompoundConcentration [%] [μg/g] [ng/ml/h] Cyproterone 0.94 89.4 ± 4.6  141 ±17  Acetate Cortexolone- 0.99  231 ± 19  1410 ± 137 17α-propionate

As can be seen from the data, cortexolone-17α-propionate permeates skinabout 3 times as much as cyproterone acetate and has a permeation ratethat is about 10 times greater than cyproterone acetate.

Example 8: Franz Cell Diffusion Test 2

Concentration of the active agent in the receiver fluid was measurednext using a system largely identical to the system in Example 7. 3human donor skin samples were used and the permeation, expressed asCumulative Permeated amount (μg/cm²), is shown in Table 13. Thisexperiment compared the anhydrous solution of Example 4a and the aqueoussolutions of Example 5. Each contained the same amount ofcortexolone-17α-propionate (5%).

TABLE 13 Anhydrous solution of Aqueous solution Time [h] Ex. 4a of Ex. 55 0.862 0.94 7 2.75 1.36 9 6.36 1.97 24 38.1 12.5 26 45.7 14.9 28 55.719.6

As is evident from the data in Table 13, water in the formulation canreduce cortexolone-17α-propionate's penetration into the skin.

Example 9: Phase 2 Clinical Study in Males with Androgenetic Alopecia(AGA)

The formulation described in Example 4b was studied in a multicenter,randomized, double-blind, phase 2 controlled study. In the study, theformulation of Example 4b (cortexolone-17α-propionate solution 5%) wascompared to vehicle solution as placebo. Both the formulation containingthe active and the vehicle formulation were applied twice-daily for 26weeks in males with androgenetic alopecia (AGA). The study was compliantwith Good Clinical Practices (GCP) for Clinical Research Studies.

Objective

The primary objective of this study was to compare the safety andefficacy of topical application of cortexolone-17α-propionate 5%solution (having the composition of Example 4b) (twice a day) and thevehicle solution (twice a day) in males with AGA.

Study Subjects

The subjects were 18 to 50 years of age and had mild to moderate AGA atthe temple and vertex regions of the scalp, with a modifiedHamilton-Norwood Scale rating of III vertex to V (IIIv, IV, V), andongoing hair loss.

Treatment

Subjects received either cortexolone-17α-propionate 5% solution orvehicle control solution depending on the allocation group and appliedthe provided formulation to the balding areas of the scalp (vertex andtemple) twice a day for 6 months.

Visits Schedule

Subjects had visits at baseline (visit 2), 1^(st) month (visit 3),2^(nd) month (visit 4), 4^(th) month (visit 5) and 6^(th) month (visit6). Subject screening (visit 1) took place within 2 weeks of baselinevisit (Visit 2). In all the study visits, all measurements for efficacyand safety endpoints were performed, with the exception of visits 2 and3, where only local tolerability assessment (LTA) and adverse events(AEs) evaluation were performed.

Study Measurements

In Table 14, the study measurements for hair loss classification,efficacy endpoints and safety endpoints are reported.

TABLE 14 Study measurements Type of assessment Study measurements Hairloss The Modified Norwood-Hamilton Scale was used classification toassess the eligibility of subjects at the Screening Visit. Subject hadto have mild to moderate AGA in temple and vertex region rating ModifiedHamilton-Norwood Scale III vertex to V (IIIv, IV, V) with ongoing hairloss to be eligible for this study. Efficacy  Standardized macrophotography to assess  Target Area Hair Counts (TAHC)  was performed atmonths 2, 4, and 6.  Standardized global photography (for Subject Self-Assessment and Investigator Global  Assessment) was performed atscreening and  months 2, 4 and 6.  Subject Self-Assessments (SSA)Questionnaires  were completed by the subject at months 2, 4  and 6. Thesubject used the baseline  standardized global photo of their scalp and compared it, side by side, with a “real time”  standardized globalphoto from the current  visit to provide a comparative assessment for Hair Growth Assessment (HGA), Hair  Growth Index (HGI), and Hair Growth Satisfaction Scale (HGSS).   1. HGA-Scalp hair growth was compared   from baseline using the following 7-point    scale: greatly decreased(−3),    moderately decreased (−2), slightly    decreased (−1), nochange    (0), slightly increased (1),    moderately increased (2), and   greatly increased (3).   2. HGI-Hair growth was compared from   baseline by three questions on a health    outcome questionnaire: [1]“Since the    start of treatment, when I look at my    thinning area, Ican see . . . (scalp)”, [2]    “Since the start of treatment, my hairnow    covers . . . (scalp)”, and [3] “Since    the start of treatment,the    appearance (thickness/quality/amount)    of the thinning area   on my head is . . . ”; were scored    using the following 7-point   scale: much less (−3), moderately    less (−2), slightly less (−1),   the same amount (0), slightly more    (1), moderately more (2),   much more (3).   3. HGSS-Hair appearance/growth was    compared frombaseline    by five questions: How satisfied    do you feel about: [1]The    overall appearance of your hair;    [2] The appearance of the   thinning area(s) within treatment    areas on your head; [3]    Theamount of scalp that can be    seen in the treatment areas;    [4]Theamount of hair in the treatment    areas; [5] The growth of hair    inthe treatment areas; were scored    using the following 7-point scale:very    dissatisfied (−3), dissatisfied (−2),    somewhat dissatisfied(−1), neutral/    neither satisfied nor dissatisfied (0),    somewhatsatisfied (1), satisfied (2),    very satisfied (3).  InvestigatorGlobal Assessment (IGA)  measuring change in scalp hair  growth. Theevaluator used a standardized  global photo (see above) of the subject's scalp taken at baseline and compared  it with the clinic visit'slive-assessment  of the subject's scalp hair growth using a  7-pointscale: greatly decreased (−3),  moderately decreased (−2),  slightlydecreased (−1), no change  (0), slightly increased (1),  moderatelyincreased (2), and  greatly increased (3). Safety Local and systemicadverse events (AEs) were assessed at each visit. Local tolerabilityassessment (LTA) of erythema, scaling, pruritus, and burning/stingingwere graded on discrete 5-point scale: none (0), minimal (1), mild (2),moderate (3), and severe (4) and performed at Baseline, and Months 1, 2,4, and 6. In addition, the investigator assessed reactions known to beassociated with topical application of steroids including skin atrophy,telangiectasia, folliculitis, hypopigmentation, and hyperpigmentationgraded on discrete 5-point scale: none (0), trace (1), mild (2),moderate (3), and severe (4).

In Table 15, the study endpoints, categorized as efficacy or safetyendpoints, are reported.

TABLE 15 Study endpoints. Type of endpoints Endpoints Efficacy Primaryendpoints:  1. Changes from Baseline in Target Area Hair Counts   (TAHC)[in number of non-vellus hairs] using   digital image analysis at Month6.  2. The subject's evaluation of treatment benefit via the   HairGrowth Assessment (HGA) question at Month 6. Secondary endpoints:  1.The subject's evaluation of treatment benefit via the   Hair GrowthIndex (HGI) and Hair Growth   Satisfaction Scale (HGSS) questionnairesat Month 6.  2. Investigator Global Assessment (IGA) at Month 6. Safety  1. Local tolerability.   2. Local and systemic AEs.

The Intent-To-Treat (ITT) population included all randomized subjects,that received at least one application of the study drug, and was theprimary population used for safety assessment. The per-protocol (PP)population was the subset of the ITT population completing the study andwithout major protocol deviations, and was considered as the primarypopulation for statistical analysis of efficacy endpoints. At the end ofthe study, the ITT was subdivided in the study groups as follows: 31subjects in cortexolone-17α-propionate solution 5% arm and 33 subjectsin vehicle solution arm. At the end of the study, the PP population wassubdivided in the study groups as follows: 23 subjects incortexolone-17α-propionate solution 5% arm and 25 subjects in vehiclesolution arm.

Changes from Baseline in Non-Vellus Target Area Hair Count (TAHC) atMonth 6 (Primary Efficacy Endpoint)

Non-vellus Target Area Hair Count (TAHC) was calculated using digitalimage analysis from standardized macro photographs collected at month 2,4 and 6. Table 16 reports the change from baseline in non-vellus TAHC atmonth 6 for the PP population: the values refer to the change, frombaseline, in the number of non-vellus hairs in a 1 cm² area of the scalpafter 6 months of treatment.

TABLE 16 Change from Baseline in Non-Vellus TAHC at Month 6. Change fromBaseline Cortexolone-17α- in Non-Vellus TAHC at propionate solution 5%Month 6 (Area: 1 cm²) (Example 4b) n Vehicle PP Population N 23 25 Mean12.7 2.9 Median 13.0 1.0 Standard Deviation 32.94 18.08 Minimum, Maximum−66.0, 86.0 −26.0, 50.0

As is demonstrated in the data above, cortexolone-17α-propionatesolution (5%) had larger changes from baseline in non-vellus TAHCcompared to vehicle at month 6. Cortexolone-17α-propionate solution 5%(according to Example 4b) had a larger mean change from baseline innon-vellus TAHC (12.7) with respect to vehicle, which had a mean changefrom Baseline in non-vellus TAHC of 2.9.

Hair Growth Assessment at Month 6

Subjects used the baseline standardized global photo of their scalp andcompared it, side by side, with a “real time” standardized global photoat month 6 to provide a comparative assessment for HGA. Subjectsevaluated hair growth using a 7-point scale. FIG. 1 depicts HGAfrequency distribution for the two treatment groups at month 6. In thefigure, negative HGA scores (−3, −2 and −1) have been grouped into aglobal HGA score named “unfavorable”; score 0 is named “no change,” andpositive scores (+1, +2 and +3) have been grouped into a global HGAscore named “favorable”. HGA scores for the PP population at month 6 arereported in Table 17.

TABLE 17 HGA scores for PP population at month 6. Cortexolone-17α-propionate solution 5% Vehicle HGA (Example 4b) Nr. of score Nr. ofsubjects (%) subjects (%) +3 1 (4.3%) 0 (0.0%) +2 3 (13.0%) 2 (8.0%) +15 (21.7%) 2 (8.0%) 0 8 (34.8%) 11 (44.0%) −1 5 (21.7%) 8 (32.0%) −2 1(4.3%) 2 (8.0%) −3 0 (0.0%) 0 (0.0%)

The proportion of subjects who rated scalp hair growth as favorable wasdirectionally larger in cortexolone-17α-propionate solution 5% (39%)compared to vehicle (16%). Of those subjects with favorable hair growth,the proportion of subjects who rated hair growth as greatly increased(+3), moderately increased (+2), and slightly increased (+1) was 4%,13%, and 22%, respectively for cortexolone-17α-propionate solution 5%,and 0%, 8%, and 8% respectively, for vehicle. The weighted average ofHGA at month 6 for both the treatment groups (PP populations) wascalculated: cortexolone-17α-propionate solution 5% had a higher HGAweighted average at month 6 (0.30) compared to placebo (−0.24).

This data demonstrates that subjects in the cortexolone-17α-propionatesolution 5% group had a larger magnitude of improvement compared tovehicle solution.

Hair Growth Index (HGI) at Month 6

Subjects used the baseline standardized global photo of their scalp andcompared it, side by side, with a “real time” standardized global photoat month 6 to provide a comparative assessment for HGI. Hair growth wascompared from baseline by three questions on a health outcomequestionnaire. The proportion of subjects who rated scalp hair growth asfavorable was larger in cortexolone-17α-propionate solution 5% (Q1: 39%,Q2: 35%, and Q3: 43%) compared to vehicle (Q1: 16%, Q2: 12%, and Q3:20%).

Hair Growth Satisfaction Scale (HGSS) at Month 6

Subjects used the baseline standardized global photo of their scalp andcompared it, side by side, with a “real time” standardized global photoat month 6 to provide a comparative assessment for HGSS. Hairappearance/growth was compared from baseline using five questions. Theproportion of subjects who were satisfied with scalp hair growth waslarger in cortexolone-17α-propionate solution 5% compared to vehiclesolution. For questions #1-5 (Q1-Q5), the proportion of subjects whorated scalp hair growth as favorable (scores of +1, +2 and +3) washigher for cortexolone-17α-propionate solution 5% (Q1: 38%, Q2-Q5: 30%)compared to vehicle solution (Q1/Q3: 8%, Q2/Q4/Q5: 20%). Forcortexolone-17α-propionate 5% solution, no subjects were ‘verydissatisfied’ (score of −3) for any of the HGSS questions at Month 6,whereas, for vehicle, there were some subjects very dissatisfied in allthe HGSS questions at month 6.

Investigator's Global Assessment (IGA) at Month 6

At month 6, investigators used a standardized global photo of thesubject's scalp taken at baseline and compared it with a live-assessmentof the subject's scalp hair growth using a 7-point scale. FIG. 2 depictsthe frequency distribution of IGA for two treatment groups (one forcortexolone-17α-propionate solution and one for vehicle solution) atmonth 6. In FIG. 2, negative IGA scores (−3, −2 and −1) are grouped intoa global IGA score named “unfavorable”; score 0 is named “no change” andpositive scores (+1, +2 and +3) are grouped into a global IGA scorenamed “favorable”. IGA scores for the PP population at month 6 arereported in Table 18.

TABLE 18 IGA scores for PP population at month 6. Cortexolone-17α-propionate solution 5% Vehicle IGA (Example 4b) Nr. of score Nr. ofsubjects (%) subjects (%) +3 0 (0.0%) 0 (0.0%) +2 3 (13.0%) 0 (0.0%) +17 (30.4%) 9 (36.0%) 0 11 (47.8%) 11 (44.0%) −1 1 (4.3%) 4 (16.0%) −2 1(4.3%) 1 (4.0%) −3 0 (0.0%) 0 (0.0%)

The proportion of subjects who had a favorable IGA score (scores of +1,+2 and +3) was higher in the cortexolone-17α-propionate solution 5%group (43%) than in the vehicle group (36%), and the proportion ofsubjects who had an unfavorable IGA score (scores of −1, −2 and −3) waslower for cortexolone-17α-propionate (9%) compared to the vehicle (20%).The weighted average of IGA at month 6 for both the treatment groups (PPpopulations) was calculated: cortexolone-17α-propionate solution 5% hada higher IGA weighted average at month 6 (0.43) compared to placebo(0.12).

This data demonstrates that subjects in the cortexolone-17α-propionatesolution 5% group had a larger magnitude of improvement compared to thevehicle solution.

Local Tolerability and Adverse Events Assessment

Local Tolerability Assessment analysis was performed on all subjectsthat applied the test article at least once (ITT population). Theincidence of each sign in the LTA was low throughout the study andgenerally similar among the treatment groups. Of the local tolerabilitysigns reported, most signs were minimal to mild in severity, with (indescending order of incidence) pruritus, scaling, erythema,folliculitis, hyperpigmentation, and hypopigmentation present aftertreatment.

The incidence of Adverse Events (AEs) was similar among the treatmentgroups, with most events typically mild in severity and not related tothe test article. In the cortexolone-17α-propionate solution 5% group,AEs occurred in 18/31 subjects (58.1%), while, in the vehicle group, AEsoccurred in 17/33 subjects (51.5%). The majority of AEs were mild. 4 AEsin vehicle group were rated as severe, with only one of them (headache)possibly related to the test article. No severe AE incortexolone-17α-propionate group occurred.

Importantly, no adverse events which could be due to a systemicantiandrogenic effect (e.g. decreased libido, erectile dysfunction,and/or ejaculation disorder) occurred in any of the patients treatedwith cortexolone-17α-propionate solution 5% for 6 months.

Conclusions

The study was a Phase II POC study in a limited number of subjects, andwas not powered to show statistically significant differences amongstudy groups; nevertheless, the study demonstrated a superiorimprovement in hair growth of cortexolone 17α-propionate solution 5%compared to vehicle: at month 6, in the PP population, cortexolone17α-propionate (12.7) had superior change from Baseline in non-vellusTarget Area Hair Count (TAHC) compared to vehicle (2.9). The result ofsubject Hair Growth Assessment questionnaire (the other primary efficacyendpoint of the study) was consistent with the quantitative TAHCmeasurements, and the proportion of subjects who rated scalp hair growthas favorable was larger in cortexolone 17α-propionate (39%) compared tovehicle (16%); of those subjects who rated scalp hair growth asfavorable, cortexolone 17α-propionate tended to have a larger magnitudeof improvement compared to vehicle. The results of the secondaryendpoints were generally consistent with that of the primary endpoints.

Example 10: 15% (w/v) Solution

A 15% (w/v) solution of cortexolone-17α-propionate having the componentsshown in Table 19, below, was prepared by solubilizing the therapeuticagent in the mixture of solvents followed by the addition of theantioxidant (ascorbyl palmitate) and the emulsifier (polysorbate 80).

TABLE 19 Amount Amount (Kg/20 Component (g/100 mL) L batch)Cortexolone-17α-propionate 15.000 3.000 Diethylene glycol monoethylether 28.000 5.600 (Transcutol ®) Alcohol (Ethanol) 28.000 5.600Ascorbyl palmitate 0.500 0.100 Polysorbate 80 0.100 0.020 Propyleneglycol Q.s. to 100 mL Q.s. to 20 L

Example 11: Comparison of the Effects of the Formulation of Example 4band the Commercially Available Finasteride 1 mg Tablet (PROPECIA®)

Based on the results of finasteride 1 mg tablets (PROPECIA®) describedin the two Phase III clinical studies published online by the UnitedStates Food and Drug Administration (the FDA), it can be concluded thatthe mean change from baseline in non-vellus TAHC at month 6 forcortexolone-17α-propionate solution 5% (according to Example 4b), asreported in Example 9, is very similar to the mean change from baselinein non-vellus TAHC at month 6 observed in 2 phase III clinical trials onfinasteride 1 mg tablets (tradename Propecia®) per os once daily. Table20 below reports the change from baseline in TAHC at month 6 in the twofinasteride studies (data of active finasteride groups) as described inthe NDA for PROPECIA® published online by the FDA:

TABLE 20 Mean change from baseline in TAHC at month 6 in the 2finasteride phase III clinical studies (data of active finasteridegroups are reported)-original data. Change from Baseline in non-vellusTAHC at Month 6 (target area: 1-inch diameter circle, corresponding toStudy 5.1 cm²) 087 69.5 089 58.4 Combined (study 087 + 089) 62.4

In the two finasteride studies, the target area was a 1-inch diametercircle, which corresponds to 5.1 cm². In order to compare the changesfrom baseline in TAHC at month 6 obtained in the finasteride studies andthe change from baseline in TAHC at month 6 obtained withcortexolone-17α-propionate in the study of the present Example 9 (wherethe target area was 1 cm²), the original finasteride data have beenrecalculated to take into account the differences between the totalsurfaces of the target areas (i.e., the values were divided by 5.1) asshown in Table 21.

TABLE 21 Mean change from baseline in TAHC at month 6 in the 2finasteride phase III clinical studies (data of active finasteridegroups are reported), recalculated over a target area of 1 cm². Changefrom Baseline in non-vellus TAHC at Month 6, recalculated Study over atarget area of 1 cm² 087 13.6 089 11.5 Combined (study 087 + 089) 12.2

Accordingly, the changes from baseline in TAHC at month 6 forfinasteride were as follows: 13.6 in study 087, 11.5 in study 089 and12.2 for the two studies combined. It is apparent that these values arealmost identical to the change from baseline in TAHC at month 6, in thePP population, for cortexolone-17α-propionate solution 5% preparedaccording to Example 4b (12.7). As discussed above, at month 6, theefficacy, measured as hair growth, of finasteride 1 mg tablets given peros once daily and of cortexolone-17α-propionate solution 5% topicallyadministered twice daily on the scalp of the patients are comparable.

The phraseology or terminology herein is for the purpose of descriptionand not of limitation. As such, the terminology and/or phraseology ofthe present specification should be interpreted by the skilled artisanin light of the teachings and guidance herein.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims and their equivalents.

All patents, patent applications, and other references noted orreferenced in this application are hereby incorporated by reference intheir entirety.

What is claimed:
 1. A method of treating acne or alopecia, the method comprising topically administering to a subject in need thereof twice daily, an effective amount of a pharmaceutical formulation comprising cortexolone-17α-propionate, wherein the twice daily administration provides a mean steady-state C_(max) of cortexolone-17α-propionate of about 2 ng/ml to about 6 ng/ml.
 2. The method of claim 1, wherein the pharmaceutical formulation is a semi-solid formulation.
 3. The method of claim 2, wherein the semi-solid formulation is a cream, a gel, a foam, or an ointment.
 4. The method of claim 3, wherein the semi-solid formulation is a cream.
 5. The method of claim 1, wherein the pharmaceutical formulation is a liquid.
 6. The method of claim 1, wherein the twice daily administration provides a mean steady-state T_(max) of cortexolone-17α-propionate of about 2 hours to about 7 hours.
 7. The method of claim 1, where the twice daily administration provides an AUC_(0-t) of from about 20 (ng*h)/ml to about 55 (ng*h)/ml.
 8. The method of claim 1, wherein urine from the subject contains a detectable amount of cortexolone-17α-propionate corresponding to less than 0.5% of the cortexolone-17α-propionate administered to the subject. 